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The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal in open access,
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Atlas of Genetics and Cytogenetics
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Volume 21, Number 7, July 2017
Table of contents
Gene Section
ATM (ataxia telangiectasia mutated) 237 Yossi Shiloh
Leukaemia Section
del (5q) solely in Myelodysplastic syndrome 249 Nahid Shahmarvand, Robert S. Ohgami
del(9p) in Acute Lymphoblastic Leukemia 252 Anwar N. Mohamed
der(X)t(X;8)(q28;q11.2) 256 Tatiana Gindina
t(1;9)(q24;q34) RCSD1/ABL1 259 Adriana Zamecnikova, Soad al Bahar
t(3;9)(p13;q34.1) FOXP1/ABL1 263 Julie Sanford Biggerstaff
t(1;22)(p36;q11) IGL/PRDM16 265 Jean-Loup Huret
t(1;3)(p36;q21) RPN1/PRDM16 267 Jean-Loup Huret
t(1;17)(p36;q21) WNT3 or NSF/PRDM16 270 Jean-Loup Huret
Cancer Prone Disease Section
Fanconi anemia 272 Filippo Rosselli
Gene Section Review
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7) 237
Atlas of Genetics and Cytogenetics in Oncology and Haematology
INIST-CNRS OPEN ACCESS JOURNAL
ATM (ataxia telangiectasia mutated) Yossi Shiloh
The David and Inez Myers Chair in Cancer Research, Department of Human Molecular Genetics and
Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; yossih+AEA-
post.tau.ac.il
Published in Atlas Database: October 2016
Online updated version : http://AtlasGeneticsOncology.org/Genes/ATMID123.html
Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68260/10-2016-ATMID123.pdf DOI: 10.4267/2042/68260
This article is an update of : Uhrhammer N, Bay JO, Gatti RA. ATM (ataxia telangiectasia mutated). Atlas Genet Cytogenet Oncol Haematol 2003;7(1) Uhrhammer N, Bay JO, Gatti RA. ATM (ataxia telangiectasia mutated). Atlas Genet Cytogenet Oncol Haematol 1999;3(4) Huret JL. ATM (ataxia telangiectasia mutated). Atlas Genet Cytogenet Oncol Haematol 1998;2(3)
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2017 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract
Review on ATM, with data on DNA, on the protein
encoded, and where the gene is implicated.
Keywords
Ataxia telangiectasia; Cerebellar ataxia;
Telangiectasia; Immunodeficiency; T- cell
malignancies; B-cell malignancies; Carcinomas;
Senescence; Chromosome instability syndrome;
DNA double-strand breaks; Translocation;
Oxidative stress; Homeostasis; ATM; chromosome.
Identity
HGNC (Hugo): ATM
Location: 11q22.3
Note
See also, in Deep Insight section: Ataxia-
Telangiectasia and variants.
DNA/RNA
ATM (11q22.3) in normal cells: PAC 1053F10 - Courtesy Mariano Rocchi, Resources for Molecular Cytogenetics.
Description
The ATM gene extends over 184 kb and contains 66
exons producing a 13 kb mRNA (Uziel T et al.,
1996; Platzer M et al., 1997); numerous Alu and
Lime sequences.
Transcription
Alternative exons 1a and 1b; initiation codon lies
within exon 4; 12 kb transcript with a 9.2 kb of
coding sequence.
The ATM promotor is bi-directional and also directs
the transcription of the NPAT gene.
Protein
Description
ATM is a homeostatic protein kinase with an
extremely broad range of roles in various cellular
circuits (Shiloh Y et al., 2013; Guleria A et al., 2016;
Shiloh Y, 2014; Cremona CA et al., 2014; Ambrose
M et al., 2013; Espach Y et al., 2015; Awasthi P et
al., 2016). This large polypeptide of 350 kDa and
3,056 residues bears a PI3 kinase signature within its
carboxy-terminal catalytic site, but has the catalytic
activity of a serine-threonine protein kinase. This
motif is characteristic of a protein family of which
ATM is a member - the PI-3 kinase-like protein
kinases (PIKKs; Lovejoy CA et al., 2009;
Bareti+ACY-cacute; D et al., 2014).
ATM (ataxia telangiectasia mutated) Shiloh Y
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7) 238
This family also contains the MTOR protein, which
regulates many signaling pathways in response to
nutrient levels, growth factors and energy balance
(Alayev A et al., 2013; Cornu M et al., 2013); the
catalytic subunit of the DNA-dependent protein
kinase (DNA-PKcs), which is involved in the NHEJ
pathway of double strand breaks (DSB) repair and
other genotoxic stress responses (Davis AJ et al.,
2014; Jette N et al., 2015), SMG1, which plays a key
role in nonsense-mediated mRNA decay (Yamashita
A, 2013); and ATR, which responds to stalled
replication forks and a variety of DNA lesions that
lead to the formation of single-stranded DNA,
including deeply resected DSBs (Errico A et al.,
2012; Mar+ACY-eacute;chal A et al., 2013; Awasthi
P et al., 2016). The redundancy, crosstalk and
collaboration between the latter three PIKKs, which
collectively respond to a broad spectrum of
genotoxic stresses, are being extensively
investigated (Lovejoy CA et al., 2009; Mar+ACY-
eacute;chal A et al., 2013; Sirbu BM et al., 2013;
Thompson LH, 2012; Gobbini E et al., 2013; Chen
BP et al., 2012).
It should be noted that in A-T patients, the two
PIKKs that converse and cooperate with ATM in the
response to genotoxic stress, ATR and DNA-PK,
remain active. In view of the functional relationships
between the three protein kinases, some of ATM's
duties are probably carried out to a certain extent by
ATR and/or DNA-PK, in A-T cells. On the other
hand, the lack of a very versatile member of this trio
may lead to some suboptimal responses of the other
two, if they depend on the crosstalk with ATM. This
interesting question is a subject of intensive research.
Expression
ATM is expressed in all tissues.
Localisation Mostly in the nucleus throughout all stages of the cell
cycle.
Function Homeostatic protein kinase involved in many
cellular circuits. A primary role in the DNA damage
response. Activated vigorously by DNA double-
strand breaks and activates a broad network of
responses. ATM initiates cell cycle checkpoints in
response to double-strand DNA breaks by
phosphorylating TP53, BRCA1, H2AFX, ABL1,
NFKBIA and CHEK1, as well as other targets; in
certain types of tissues ATM inhibits radiation-
induced, TP53-dependent apoptosis.
Double strand breaks The most widely
documented function of ATM, and the one
associated with its most vigorous activation, is the
mobilization of the complex signaling network that
responds to DSBs in the DNA (Shiloh Y et al., 2013;
Cremona CA et al., 2014; Awasthi P et al., 2016;
Thompson LH, 2012; McKinnon PJ, 2012). DSBs
are induced by exogenous DNA breaking agents or
endogenous reactive oxygen species (Schieber M et
al., 2014), and are an integral part of physiological
processes including meiotic recombination (Borde V
et al., 2013; Lange J et al., 2011) and the
rearrangement of antigen receptor genes in the
adaptive immune system (Alt FW et al., 2013).
DSBs are repaired via nonhomologous end-joining
(NHEJ), or homologous recombination repair (HRR;
Shibata A et al., 2014; Chapman JR et al., 2012;
Jasin M et al., 2013; Radhakrishnan SK et al., 2014).
DSBs also activates the DDR, a vast signaling
network that mobilizes special cell cycle
checkpoints, extensively alters the cellular
transcriptome, and changes the turnover, activity and
function of numerous proteins that ultimately leads
to modulation of numerous cellular circuits. This
network is based on a core of dedicated DDR players
and the ad-hoc recruitment of proteins from many
other arenas of cellular metabolism, which typically
undergo special, damage-induced post-translational
modifications (PTMs; Shiloh Y et al., 2013; Sirbu
BM et al., 2013; Thompson LH, 2012) (Goodarzi
AA et al., 2013; Panier S et al., 2013; Polo SE et al.,
2011).
Once ATM mobilizes the vast DDR network in
response to a DSB (McKinnon PJ, 2012; Shiloh Y et
al., 2013; Bhatti S et al., 2011), its protein kinase
activity is rapidly enhanced, and PTMs on the ATM
molecule are induced, including several
autophosphorylations and an acetylation (Shiloh Y et
al., 2013; Bhatti S et al., 2011; Bakkenist CJ et al.,
2003; Kozlov SV et al., 2006; Bensimon A et al.,
2010; Sun Y et al., 2007; Kaidi A et al., 2013; Paull
TT, 2015).
ATM subsequently phosphorylates key players in
various arms of the DSB response network (Shiloh
Y et al., 2013; Bensimon A et al., 2010; Matsuoka S
et al., 2007; Mu JJ et al., 2007; Bensimon A et al.,
2011), including other protein kinases that in turn
phosphorylate still other targets (Bensimon A et al.,
2011).
Single-strand break repair and base excision
repair A broader, overarching role for ATM in
maintaining genome stability was recently suggested
in addition to mobilizing the DSB response (Shiloh
Y, 2014). According to this conjecture, ATM
supports other DNA repair pathways that respond to
various genotoxic stresses, among them single-
strand break repair (SSBR; Khoronenkova SV et al.,
2015) and base excision repair (BER) - a cardinal
pathway in dealing with the daily nuclear and
mitochondrial DNA damage caused by endogenous
agents (Wallace SS, 2014; Bauer NC et al., 2015).
ATM's involvement in these processes is based on its
ability to phosphorylate proteins that function in
these pathways. In this way ATM also takes part also
in resolving non-canonical DNA structures that arise
ATM (ataxia telangiectasia mutated) Shiloh Y
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7) 239
in DNA metabolism, and in regulating other aspects
of genome integrity such as nucleotide metabolism,
the response to replication stress, and resolution of
the occasional conflicts that arise between DNA
damage and the transcription machinery. ATM is not
critical for any of these processes in the same way it
is for the DSB response, but rather contributes to
their regulation (in most cases, their enhancement)
when the need arises (Shiloh Y, 2014; Segal-Raz H
et al., 2011; Zolner AE et al., 2011).
This function of ATM may explain the moderate,
variable sensitivity of ATM-deficient cells to a broad
range of DNA damaging agents. Among them are
UV radiation, alkylating agents, crosslinking agents,
hydrogen peroxide, 4-Nitroquinoline 1-oxide,
phorbol-12-myristate-13-acetate and topoisomerase
1 poisons (Yi M et al., 1990; Ward AJ et al., 1994;
Hoar DI et al., 1976; Paterson MC et al., 1976; Smith
PJ et al., 1980; Mirzayans R et al., 1989; Henderson
EE et al., 1980; Scudiero DA, 1980; Jaspers NG et
al., 1982; Teo IA et al., 1982; Barfknecht TR et al.,
1982; Fedier A et al., 2003; Leonard JC et al., 2004;
Lee JH et al., 2006; Zhang N et al., 1996; Smith PJ
et al., 1989; Alagoz M et al., 2013; Katyal S et al.,
2014; Speit G et al., 2000; Shiloh Y et al., 1985;
Hannan MA et al., 2002).
ATM-deficient cells also exhibit reduced efficiency
in resolving TOP1 (Topoisomerase I) -DNA
covalent intermediates (Alagoz M et al., 2013;
Katyal S et al., 2014).
This ongoing role of ATM is its routine function in
the daily maintenance of genome stability, while its
powerful role in the DSB response is reserved for
when this harmful lesion interferes with the daily life
of a cell. Thus, when ATM is missing, not only is
there markedly reduced response to DSBs, the
ongoing modulation of numerous pathways in
response to occasional stresses becomes suboptimal.
All of these lesions are part of the daily wear and tear
on the genome that contributes to ageing.
An additional role for ATM in genome dynamics
was proposed following evidence that ATM is
involved in shaping the epigenome in neurons by
regulating the localization of the histone deacetylase
4 (HDAC4 Li J et al., 2012; Herrup K et al., 2013;
Herrup K, 2013), targeting the EZH2 component of
the polycomb repressive complex 2 (Li J et al.,
2013), and regulating the levels of 5-
hydroxymethylcytosine in Purkinje cells (Jiang D et
al., 2015).
Oxidative stress/Cellular homeostasis.
Cytoplasmic fraction of ATM ATM's role in
cellular homeostasis is further expanded by its
cytoplasmic fraction. Specifically, cytoplasmic
ATM was found to be associated with peroxisomes
(Watters D et al., 1999; Tripathi DN et al., 2016;
Zhang J et al., 2015) and mitochondria (Valentin-
Vega YA et al., 2012). In view of the evidence of
increased oxidative stress in ATM-deficient cells, it
has long been suspected that ATM senses and
responds to oxidative stress (Gatei M et al., 2001;
Rotman G et al., 1997; Rotman G et al., 1997;
Barzilai A et al., 2002; Watters DJ, 2003; Takao N
et al., 2000; Alexander A et al., 2010). This
conjecture was validated by work from the Paull lab
(Guo Z et al., 2010a), which identified an MRN-
independent mode of ATM activation,
differentiating it from DSB-induced activation,
stimulated by reactive oxygen species (ROS) and
leading to ATM oxidation (Paull TT, 2015; Guo Z et
al., 2010a; Guo Z et al., 2010b; Lee JH et al., 2014).
ATM was also found to be involved specifically in
the protection against oxidative stress induced by
oxidized low-density lipoprotein (Semlitsch M et al.,
2011). It has thus assumed the role of a redox sensor
(Ditch S et al., 2012; Tripathi DN et al., 2016;
Kr+ACY-uuml;ger A et al., 2011). Recently, the first
phospho-proteomic screen was carried out to
identify substrates of ROS-activated ATM (Kozlov
SV et al., 2016). An important arm of the ATM-
mediated response to ROS extends to peroxisomes
(Tripathi DN et al., 2016). Work from the Walker lab
showed that ROS-mediated activation of
peroxisomal ATM leads to ATM-mediated
phosphorylation of LKB and subsequent activation
of AMPK and TSC2, which dampens mTORC1-
mediated signaling, eventually decreasing protein
synthesis and enhancing autophagy (Alexander A et
al., 2010; Tripathi DN et al., 2013; Zhang J et al.,
2013; Alexander A et al., 2010; Alexander A et al.,
2010).
Further work from this lab (Zhang J et al., 2015)
showed that ATM also phosphorylates the
peroxisomal protein PEX5, flagging it for
ubiquitylation and subsequent binding to the
autophagy adapter, SQSTM1 (p62), in the process of
autophagy-associated peroxisome degradation
(pexophagy) - a critical process in peroxisome
homeostasis (Till A et al., 2012).
Mitochondrial fraction of ATM. Still another arm
of the ATM-mediated response to oxidative stress
operates in the mitochondrial fraction of ATM. ATM
is thus emerging also as a regulator of mitochondrial
homeostasis. Evidence is accumulating of its
involvement in mitochondrial function, mitophagy,
and the integrity of mitochondrial DNA (Valentin-
Vega YA et al., 2012; Ambrose M et al., 2007; Eaton
JS et al., 2007; Fu X et al., 2008; Valentin-Vega YA
et al., 2012; D'Souza AD et al., 2013; Sharma NK et
al., 2014) and further work is needed to identify its
substrates in mitochondria and the mechanistic
aspects of its action in this arena.
Links between ATM and the SASP (senescence-
associated secretory phenotype). Several
laboratories recently described direct links between
ATM and the SASP - a cardinal feature of cell
senescence. Work from the Gamble lab (Chen H et
al., 2015) showed that the histone variant
ATM (ataxia telangiectasia mutated) Shiloh Y
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7) 240
macroH2A.1 is required for full transcriptional
activation of SASP-promoting genes, driving a
positive feedback loop that enhances cell
senescence. This response is countered by a negative
feedback loop that involves ATM activation by
endoplasmic reticulum stress, elevated ROS levels
or DNA damage. ATM's activity is required for the
removal of macroH2A.1 from sites of SASP genes,
thus leading to SASP gene repression. The Elledge
lab identified a major SASP activator - the
transcription factor GATA4 ID, whose stabilization
drives this process (Kang C et al., 2015).
Importantly, the activation of this pathway was
dependent on both ATM and ATR, as was
senescence-associated activation of TP53 and
CDKN2A (p16INK4a). On the other hand, the
Zhang lab (Aird KM et al., 2015) recently showed
that when cell senescence is induced by replication
stress (e.g., following nucleotide deficiency), ATM
inactivation allows the cell to bypass senescence by
shifting cellular metabolism: upon ATM loss, dNTP
levels rise due to up-regulation of the pentose
phosphate pathway, whose key regulator, glucose-6-
phosphate dehydrogenase (G6PD) is under
functional regulation by ATM (Aird KM et al., 2015;
Cosentino C et al., 2011).
Insulin response and lipoprotein metabolism. Other metabolic arenas in which ATM involvement
is gaining attention are insulin response and
lipoprotein metabolism, clinically represented by the
metabolic syndrome. This role of ATM in cellular
physiology was recently thoroughly and
convincingly reviewed (Espach Y et al., 2015).
Briefly, ATM was found to participate in several
signaling pathways mediated by insulin (Yang DQ et
al., 2000; Miles PD et al., 2007; Viniegra JG et al.,
2005; Halaby MJ et al., 2008; Jeong I et al., 2010);
and heterozygosity for Atm null allele in ApoE-
deficient mice was found to aggravate their
metabolic syndrome (Wu D et al., 2005; Schneider
JG et al., 2006; Mercer JR et al., 2010), an effect that
was partly relieved by the mitochondria-targeted
antioxidant MitQ (Mercer JR et al., 2012.
IGF-1 receptor. Another pathway by which ATM
may impact on cellular senescence is the dependence
of IGF1R (IGF-1 receptor) expression on ATM
(Peretz S et al., 2001; Goetz EM et al., 2011; Ching
JK et al., 2013); the mechanism remains to be
elucidated, but ATM impacts on IGF-1-mediated
pathways, including those that affect cellular
senescence (Luo X et al., 2014).
Beta-adrenergic receptor. Another series of
observations assigned ATM a protective role in
cardiac myocyte apoptosis stimulated by +ACY-
beta;-adrenergic receptor and myocardial
remodeling. Loss of Atm in mice induced
myocardial fibrosis and myocyte hypertrophy and
interfered with cardiac remodeling following
myocardial infarction (Foster CR et al., 2011; Foster
CR et al., 2012; Foster CR et al., 2013; Daniel LL et
al., 2014). The mechanistic aspects of these effects
are still unclear, but ATM's apparent involvement in
myocardial homeostasis might be relevant to the
observation of elevated arteriosclerosis in A-T
carriers (Swift M et al., 1983; Su Y et al., 2000).
Homology
Phosphatidylinositol 3-kinase (PI3K)-like proteins,
most closely related to ATR and the DNA-PK
catalytic subunit.
Mutations
The cellular phenotype of A-T represents genome
instability, deficient DNA damage response (DDR),
and elevated oxidative stress, in addition to a
premature senescence component (Shiloh Y et al.,
1982).
Germinal Various types of mutations have been described,
dispersed throughout the gene, and therefore most
patients are compound heterozygotes; most
mutations appear to inactivate the ATM protein by
truncation, large deletions, or annulation of initiation
or termination, although missense mutations have
been described in the PI3 kinase domain and the
leucine zipper motif.
Patients with the severe form of A-T are
homozygous or compound heterozygous for null
ATM alleles. The corresponding mutations usually
lead to truncation of the ATM protein and
subsequently to its loss due to instability of the
truncated derivatives; a smaller portion of the
mutations create amino acid substitutions that
abolish ATM's catalytic activity (Taylor AM et al.,
2015; Gilad S et al., 1996; Sandoval N et al., 1999;
Barone G et al., 2009).
Careful inspection of the neurological symptoms of
A-T patients reveals variability in their age of onset
and rate of progression among patients with different
combinations of null ATM alleles (Taylor AM et al.,
2015; Crawford TO et al., 2000; Alterman N et al.,
2007). Thus, despite the identical outcome in terms
of ATM function, additional genes may affect the
most cardinal symptom of A-T. Other, milder types
of ATM mutations further extend this variability,
and account for forms of the disease with extremely
variable severity and age of onset of symptoms. The
corresponding ATM genotypes are combinations of
hypomorphic alleles or combinations of null and
hypomorphic ones. Many of the latter are leaky
splicing mutations and others are missense
mutations, eventually yielding low amounts of active
ATM (Taylor AM et al., 2015; Alterman N et al.,
2007; Soresina A et al., 2008; Verhagen MM et al.,
2009; Silvestri G et al., 2010; Saunders-Pullman R
et al., 2012; Verhagen MM et al., 2012; Worth PF et
al., 2013; Claes K et al., 2013; M+ACY-eacute;neret
ATM (ataxia telangiectasia mutated) Shiloh Y
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7) 241
A et al., 2014; Nakamura K et al., 2014; Gilad S et
al., 1998).
Somatic
B A variety of missense somatic, biallelic mutations
were identified in hematologic malignancies, most
notably mantle cell lymphomaand T-
prolymphocytic leukaemia. Missense mutations
outside of the PI3 kinase and leucine zipper domains
have been described among breast cancer patients,
although these mutations have not been found in A-
T patients. Whether these mutations contribute to
breast cancer though not to ataxia-telangiectasia
remains controversial.
Implicated in
Ataxia telangiectasia
Note
Ataxia telangiectasia is a prototype genome
instability syndrome (Perlman SL et al., 2012; Lavin
MF, 2008; Crawford TO, 1998; Chun HH et al.,
2004; Taylor AM et al., 1982; Taylor AM et al.,
2015; Taylor AM, 1978; Butterworth SV et al.,
1986; Kennaugh AA et al., 1986).
Disease
Ataxia telangiectasia is a progressive cerebellar
degenerative disease with telangiectasia,
immunodeficiency, premature aging , cancer risk,
radiosensitivity, and chromosomal instability.
Prognosis
Prognosis is poor: median age at death: 17 years;
survival rarely exceeds 30 years, though survival is
increasing with improved medical care.
Cytogenetics
Spontaneous chromatid/chromosome breaks; non
clonal stable chromosome rearrangements involving
immunoglobulin superfamilly genes e.g.
inv(7)(p14q35); clonal rearrangements.
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This article should be referenced as such:
Shiloh Y. ATM (ataxia telangiectasia mutated). Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7):237-248.
Leukaemia Section Short Communication
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7) 249
Atlas of Genetics and Cytogenetics in Oncology and Haematology
INIST-CNRS OPEN ACCESS JOURNAL
del (5q) solely in Myelodysplastic syndrome Nahid Shahmarvand, Robert S. Ohgami
Department of Pathology, Stanford University, Stanford, CA, USA;
Published in Atlas Database: October 2016
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/del5qSoleID1134.html
Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68261/10-2016-del5qSoleID1134.pdf DOI: 10.4267/2042/68261
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2017 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract Review on Myelodysplastic syndrome with isolated
deletion of 5q
Keywords
Myelodysplastic syndrome; chromosome 5; deletion
5q
Identity
del (5q) solely in Myelodysplastic syndrome
Other names
Myelodysplastic syndrome with isolated deletion of
5q
Clinics and pathology
Disease
Myelodysplastic syndrome (MDS) with isolated
deletion of chromosome 5q is part of a group of
clonal disorders in myeloid stem cells with
ineffective hematopoiesis which is manifested by
morphologic dysplasia in hematopoietic cells and
single or bilineage cytopenia(s). It is the only MDS
subtype defined cytogenetically in the World Health
Organization classification system.
Phenotype/cell stem origin
Myeloid stem cell.
Epidemiology
MDS with isolated del(5q) is present in <5% of MDS
cases (Mallo et al., 2011). It occurs more often in
women than in men, male:female ratio 7:3,
with a median age of diagnosis at 65 to 70 years.
Clinics
Patients suffering from MDS with isolated del(5q)
present with a macrocytic anemia, normal or
increased platelet count and absence of significant
neutropenia in their peripheral blood. The incidence
of bleeding and infections is therefore low in these
patients because of the absence of significant
neutropenia and thrombocytopenia. Blood
transfusion dependency is seen in patients with
severe anemia at diagnosis but also can develop in
other patients (Germing et al., 2012). According to
the Revised International Prognostic Scoring System
(IPSS-R), MDS with isolated del(5q) are defined as
Low- or Intermediate -1- risk subtypes and usually
have an indolent course.
Pathology
The bone marrow is characterized by an increase in
the number of small megakaryocytes with
monolobulated and bilobulated nuclei. There are less
than 1% blasts in the peripheral blood and less than
5% blasts in the bone marrow and Auer Rods are
absent (Arber et al., 2016).
Treatment
MDS patients with isolated del(5q) have a favorable
prognosis and the majority of patients respond well
to treatment with lenalidomide.
Prognosis
This subtype of MDS has a favorable prognosis. The
exception is when this disease is associated with
mutations in TP53.
del (5q) solely in Myelodysplastic syndrome Shahmarvand N, Ohgami RS
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7) 250
Figure 1: An example of a typical hypolobated micromegakaryocyte in a bone marrow aspirate smear. (Wright-Giemsa)
Cytogenetics
Cytogenetics morphological
As its name implies, in this entity there is interstitial
deletion of part of the long arm of chromosome 5
involving 5q31-5q33. MDS with isolated del(5q) can
still be diagnosed if there is 1 additional cytogenetic
abnormality besides del(5q) if there is no adverse
effect of that abnormality, as such, this excludes
{CC: TXT:monosomy 7 or del 7(q) ID:} for instance
(Arber et al., 2016).
Cytogenetics molecular
The gene specific for the defect seen in MDS with
isolated del(5q) has been identified by RNA
interference screening to be RPS14 (Pellagatti et al.,
2008).
In addition, while patients with MDS with isolated
del(5q) classically have a favorable prognosis, the
presence of a TP53 mutation is of particular
importance, this mutation predicts for poorer
prognosis and higher risk of transformation to AML
(Mallo et al.,2013).
Figure 2: The karyotype in a case of MDS with isolated del(5q) showing 46,XX,del(5)(q22q35). Image courtesy of Dana Bangs, CG(ASCP), Stanford University.
del (5q) solely in Myelodysplastic syndrome Shahmarvand N, Ohgami RS
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7) 251
Genes involved and proteins
RPS14 (ribosomal protein S14)
Location
5q33.1
Protein
RPS14 is a ribosomal gene located in commonly
deleted region (CDR) of 5q. It encodes for a protein
required for maturation of 40S ribosomal subunits.
Patients with MDS with del(5q) are haploinsufficient
for RPS14 which leads to impairment of ribosome
biogenesis and subsequent reduction of protein
translation.
TP53 (Tumour protein p53 (Li-Fraumeni syndrome))
Location
17p13.1
Protein
The TP53 gene encodes for the tumor suppressor
protein p53. In the presence of DNA -damage p53
may be activated to fix the damage, or if the damage
cannot be repaired p53 prevents the cell from
dividing and signals the cell to undergo apoptosis.
References Arber DA, Hasserjian RP. Reclassifying myelodysplastic syndromes: what's where in the new WHO and why. Hematology Am Soc Hematol Educ Program. 2015;2015:294-8
Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, Bloomfield CD, Cazzola M, Vardiman JW. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016 May 19;127(20):2391-405
Bejar R. Clinical and genetic predictors of prognosis in myelodysplastic syndromes. Haematologica. 2014 Jun;99(6):956-64
Germing U, Lauseker M, Hildebrandt B, Symeonidis A, Cermak J, Fenaux P, Kelaidi C, Pfeilstöcker M, Nösslinger T, Sekeres M, Maciejewski J, Haase D, Schanz J, Seymour J, Kenealy M, Weide R, Lübbert M, Platzbecker U, Valent P, Götze K, Stauder R, Blum S, Kreuzer KA,
Schlenk R, Ganser A, Hofmann WK, Aul C, Krieger O, Kündgen A, Haas R, Hasford J, Giagounidis A. Survival, prognostic factors and rates of leukemic transformation in 381 untreated patients with MDS and del(5q): a multicenter study. Leukemia. 2012 Jun;26(6):1286-92
Jädersten M, Saft L, Smith A, Kulasekararaj A, Pomplun S, Göhring G, Hedlund A, Hast R, Schlegelberger B, Porwit A, Hellström-Lindberg E, Mufti GJ. TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression. J Clin Oncol. 2011 May 20;29(15):1971-9
Mallo M, Cervera J, Schanz J, Such E, García-Manero G, Luño E, Steidl C, Espinet B, Vallespí T, Germing U, Blum S, Ohyashiki K, Grau J, Pfeilstöcker M, Hernández JM, Noesslinger T, Giagounidis A, Aul C, Calasanz MJ, Martín ML, Valent P, Collado R, Haferlach C, Fonatsch C, Lübbert M, Stauder R, Hildebrandt B, Krieger O, Pedro C, Arenillas L, Sanz MÁ, Valencia A, Florensa L, Sanz GF, Haase D, Solé F. Impact of adjunct cytogenetic abnormalities for prognostic stratification in patients with myelodysplastic syndrome and deletion 5q. Leukemia. 2011 Jan;25(1):110-20
Mallo M, Del Rey M, Ibáñez M, Calasanz MJ, Arenillas L, Larráyoz MJ, Pedro C, Jerez A, Maciejewski J, Costa D, Nomdedeu M, Diez-Campelo M, Lumbreras E, González-Martínez T, Marugán I, Such E, Cervera J, Cigudosa JC, Alvarez S, Florensa L, Hernández JM, Solé F. Response to lenalidomide in myelodysplastic syndromes with del(5q): influence of cytogenetics and mutations. Br J Haematol. 2013 Jul;162(1):74-86
Patnaik MM, Lasho TL, Finke CM, Knudson RA, Ketterling RP, Chen D, Hoyer JD, Hanson CA, Tefferi A. Isolated del(5q) in myeloid malignancies: clinicopathologic and molecular features in 143 consecutive patients. Am J Hematol. 2011 May;86(5):393-8
Pellagatti A, Hellström-Lindberg E, Giagounidis A, Perry J, Malcovati L, Della Porta MG, Jädersten M, Killick S, Fidler C, Cazzola M, Wainscoat JS, Boultwood J. Haploinsufficiency of RPS14 in 5q- syndrome is associated with deregulation of ribosomal- and translation-related genes. Br J Haematol. 2008 Jul;142(1):57-64
Saft L, Karimi M, Ghaderi M, Matolcsy A, Mufti GJ, Kulasekararaj A, Göhring G, Giagounidis A, Selleslag D, Muus P, Sanz G, Mittelman M, Bowen D, Porwit A, Fu T, Backstrom J, Fenaux P, MacBeth KJ, Hellström-Lindberg E. p53 protein expression independently predicts outcome in patients with lower-risk myelodysplastic syndromes with del(5q). Haematologica. 2014 Jun;99(6):1041-9
This article should be referenced as such:
Shahmarvand N, Ohgami RS. del (5q) solely in Myelodysplastic syndrome. Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7):249-251.
Leukaemia Section Short Communication
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7) 252
Atlas of Genetics and Cytogenetics in Oncology and Haematology
INIST-CNRS OPEN ACCESS JOURNAL
del(9p) in Acute Lymphoblastic Leukemia Anwar N. Mohamed
Cytogenetics Laboratory, Pathology Department, Detroit Medical Center, Wayne State University
School of Medicine, Detroit, MI USA. [email protected]
Published in Atlas Database: September 2016
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/del9pALLID1064.html
Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68262/09-2016-del9pALLID1064.pdf DOI: 10.4267/2042/68262
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2017 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract Review on del(9p) in acute lymphoblastic leukemia,
with data on clinics, and the genes involved.
Keywords
chromosome 9; del(9p); acute lymphoblastic
leukemia
Identity
Deletion of 9p is a common recurring chromosomal
aberration in acute lymphoblastic leukemia (ALL) of
both B- and T-lineages ALL. The 9p region contains
numerous cancer-associated genes such as JAK2,
CD274 (PDL1)/ PDCD1LG2 (PDL2) at 9p24.1,
CDKN2A, CDKN2B, MTAP, IFN, MLLT3, and
HACD4 (PTPLAD2) at 9p21.3 as well as PAX5 at
9p13.2. Several of these genes have been implicated
in the leukemogenesis of ALL (Mullighan CG 2012,
Harrison CJ 2013).
Clinics and pathology
Disease
Acute lymphoblastic leukemia (ALL)
Epidemiology
Visible deletions of 9p by karyotype are seen in
approximately 10% of ALL cases of both children
(7-11%) and adult (5-15%). The loss of 9p is the
second most frequent abnormality after t(9;22)/Ph in
adult ALL, and the third after high
hyperdiploidy and t(12;21) inpediatric ALL
(Moorman et al 2010). The minimal commonly
deleted segment is band 9p21 encompassing the
tumor suppressor genes CDKN2A and CDKN2B.
Clinics
At diagnosis patients are likely to have higher WBC
counts, older age, male gender, splenomegaly, and
hypodiploid karyotype than patients lacking 9p
deletions (Heerema et al 1999). In addition, patients
with a 9p abnormality have an increasing incidence
of both marrow and central nervous system relapses.
Prognosis
The prognostic significance of 9p21/CDKN2A
deletion has remained indecisive particularly in
pediatric B-ALL. The differences in patient
population and study designs among different
studies may have had an impact on the overall
results.
In Pediatric B-ALL Initial studies on a small
number of patients suggested that deletion of
9p/CDKN2A was associated with an increased risk
of relapse and death although other report concluded
no prognostic effect on the disease outcome (Kees et
al 1997, Zhou et al 1997). On a large cohort study,
Heerema et al showed a high frequency of 9p
abnormalities in ALL patients with high-risk or
lymphomatous features, and an overall poorer
outcome compared with those lacking this
abnormality. Their data also indicated that 9p
abnormalities identify a subgroup of NCI standard-
risk patients with increased risk of treatment failure.
del(9p) in Acute Lymphoblastic Leukemia Mohamed AN
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7) 253
Figure 1; Top: Partial G-banded karyotype showing partial deletion 9p, der(9;16)(q10;p10), i(9(q10) [left to right]. Bottom: FISH on metaphase cell (left) and interphase cell (right) showing one copy of CDKN2A (orange signal) and two copies of CEP 9 (green
signal)
Yet, the recent study by Sulong et al concluded that
CDKN2A deletion is a significant secondary genetic
abnormality and variation in the incidence of
CDKN2A deletion among the cytogenetic subgroups
may explain its inconsistent association with
outcome.
Conversely, the dicentric (9;12) has been associated
with a favorable outcome in pediatric ALL.
In Adult B-ALL Patients with 9p deletions have
significantly shorter overall survival when compared
with patients with normal karyotypes. The overall
survival is similar to that in the poor prognosis t(9;22
)/ BCR/ ABL1-positive group (Nahi et al 2008).
In T-ALL The prognostic implications of loss of
heterozygosity (LOH) of 9p were evaluated in
pediatric T-ALL patients treated uniformly
according to the Berlin-Frankfurt-Munster regimen.
This study showed that LOH of 9p was associated
with a favorable initial treatment response, and the
event free survival was slightly favorable (Krieger et
al 2010).
Cytogenetics
Cytogenetics morphological The loss of material from 9p can result from a simple
deletion in approximately 40% of cases or from
various unbalanced translocations giving rise to a
partial or complete loss of 9p such as isochromsome
i(9)(q10), dicentric dic(9;12) and dic(9;20), whole
arm der(V;9q10), and add(9p) [Figure 1].
The majority of 9p deletions are associated with a
nonhyperdiploid karyotype (Heerema et al 1999).
Although deletion of 9p occurs as a sole abnormality
in ~20% of cases, it is frequently accompanied by
other primary genetic abnormalities such as
t(1;19)(q23;p13.3), t(9;22)(q34;q11.2),
t(12;21)(p13;q22), t(14q32) and inv(14)(q11.2q32)
suggesting that 9p deletion is a secondary change.
Deletions of 9p often are not easily detected by G-
banding.
Therefore, FISH testing targeting the CDKN2A gene
provides an excellent method for detecting the
majority of these deletions.
In large series studies, the frequency of CDKN2A/B
deletions has been reported in 20%-34% of B- ALL
but is significantly higher among T-ALL patients
50%-80%.
The distribution of 9p deletion among the
cytogenetic subgroups varies. Patients with t(9;22)
and t(1;19) have higher incidences of CDKN2A/B
deletion (40%-60%) than patients with high
hyperdiploidy, ETV6/ RUNX1 fusion , or KMT2A
(MLL)/11q23 rearrangements (11%-15%).
Both monoallelic and biallelic CDKN2A deletions
are found in ALL with the latter being more
prevalent in T-ALL (Sulong et al, 2009).
The deletions vary in size considerably from <1 Mb
to 39 Mb, and the biallelic deletions consist of a large
and small deletion. In contrast, inactivation of
CDKN2A gene in ALL by mutation or
hypermethylation appears to be low, ranging from 0-
7%.
Genes involved and proteins
del(9p) in Acute Lymphoblastic Leukemia Mohamed AN
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7) 254
CDKN2A (cyclin dependent kinase 2a / p16)
Location
9p21.3
Note
CDKN2A (Cyclin Dependent Kinase Inhibitor 2A),
alternative symbols included CDKN2, CDK4
inhibitor, multiple tumor suppressor 1(MTS1),
TP16, p16(INK4), p16(INK4A)
DNA/RNA
CDKN2A consists of three coding exons spanning
over 30kb.
Protein
CDKN2A gene encodes two major proteins
p16(INK4) and p14(ARF) through the use of shared
coding regions and alternative reading frames. Both
act as tumor suppressors by regulating the cell cycle.
The p16 prevents progression through the G1 cell
cycle checkpoint by inhibiting cyclin-dependent
kinases CDK4 and CDK6 to inactivate the
retinoblastoma ( RB1) family of tumor suppressor
proteins.
The p14 protein acts primarily by deterring MDM2
and therefore, promotes p53 protein, consequently
inducing cell cycle arrest in both G1 and G2/M
phases as well as initiating apoptosis.
Somatic mutations
Somatic mutations of CDKN2A are common in
human cancers, with estimates that CDKN2A is the
second most commonly inactivated gene in cancer
after TP53.
Germline mutations of CDKN2A are associated with
familialmelanoma, glioblastoma and pancreatic
cancer.
CDKN2B (cyclin-dependent kinase inhibitor 2B (p15, inhibits CDK4))
Location
9p21.3
Note
CDKN2B (Cyclin-Dependent Kinase Inhibitor 2B),
alternative symbols included; Multiple Tumor
Suppressor 2 (MTS2), p15(INK4B), TP15,
CDKN4B inhibitor.
Protein
CDKN2B encodes a cyclin-dependent kinase
inhibitor "p15", which forms a complex with CDK4
or CDK6, and prevents the activation of the CDK
kinases.
The p15 protein functions as a cell growth regulator
that controls cell cycle G1 progression.
Somatic mutations
CDKN2B is tandemly linked to CDKN2A and
frequently deleted in a significant proportion of
ALL, but always in association with CDKN2A.
PAX5 (paired box gene 5)
Location
9p13.2
Note
PAX5 (Paired Box Gene 5), alternative symbols
ALL3, BSAP
Protein
PAX5 gene encodes a B-cell-specific activator
protein (BSAP), which is a member of a class of
transcription factors that contains a DNA-binding
domain. It is the only member of PAX family
expressed in the hematopoietic system exclusively in
B-cells. Expression of PAX5 is initiated in pre-pro-
B cells and maintained throughout subsequent stages
of B-cell development before it is down-regulated in
plasma cell. It functions both as a transcriptional
activator and as a repressor on different target genes,
which are involved in B-lineage development.
Germinal mutations
Recently germline mutation of PAX5 gene was
identified by exome sequencing in two unrelated
families. The affected family members had B-cell
precursor ALL and the diagnostic and relapse
leukemic samples from both families demonstrated
deletion of 9p through i(9)(q10) or dicentric (9q;v),
both of which resulted in loss of the wild-type PAX5
allele and retention of mutated PAX5. The loss
resulted in a marked reduction of normal PAX5
activity in the leukemia cells.
Somatic mutations
Somatic alterations of PAX5 gene due to deletions,
point mutations, or translocations occur in
approximately 30% of B-ALL and in up to 50% of
the high-risk BCR-ABL1 positive and Ph-like ALL
subtypes. Alterations of PAX5 are not associated
with an adverse outcome in children or adult B-cell
ALL (Mullighan et al 2012, Shahjahani et al 2015).
JAK2 (janus kinase 2)
Location
9p24.1
Note
JAK2 (Janus kinase 2 gene), alternative symbol
JTK10.
Protein
JAK2 encodes a non-receptor tyrosine kinase that is
involved in a specific subset of cytokine receptor
signaling pathways. It has been found to be
constitutively associated with the prolactin receptor
(PRLR) and is required for responses to gamma
interferon ( IFNG). Upon receptor activation JAK2
phosphorylate the transcription factors "STATs" and
initiate the JAK-STAT signaling pathway.
Somatic mutations
Mutations of JAK1/2 have been identified in 18%-
35% Down syndrome - ALL and also occur in about
del(9p) in Acute Lymphoblastic Leukemia Mohamed AN
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7) 255
10% of high-risk pediatric B- ALL patients causing
a constitutive activation of the JAK-STAT pathway.
The most frequent site of mutation is at R683 in the
pseudokinase domain of JAK2 which is distinct from
the JAK2 V617F predominant mutation seen in
polycythemia vera and other myeloproliferative
neoplasms (Robert et al 2012, Hunger and Mullighan
2015). The presence of JAK mutations is
significantly associated with alteration of IKZF1 and
rearrangement of CRLF2 signifying a high risk
disease and poor outcome. ALL cases harboring
CRLF2 and JAK alterations may benefit from JAK
inhibitors targeted therapy.
References Harrison CJ. Targeting signaling pathways in acute lymphoblastic leukemia: new insights. Hematology Am Soc Hematol Educ Program. 2013;2013:118-25
Heerema NA, Sather HN, Sensel MG, Liu-Mares W, Lange BJ, Bostrom BC, Nachman JB, Steinherz PG, Hutchinson R, Gaynon PS, Arthur DC, Uckun FM. Association of chromosome arm 9p abnormalities with adverse risk in childhood acute lymphoblastic leukemia: A report from the Children's Cancer Group. Blood. 1999 Sep 1;94(5):1537-44
Hunger SP, Mullighan CG. Redefining ALL classification: toward detecting high-risk ALL and implementing precision medicine. Blood. 2015 Jun 25;125(26):3977-87
Kees UR, Burton PR, Lü C, Baker DL. Homozygous deletion of the p16/MTS1 gene in pediatric acute lymphoblastic leukemia is associated with unfavorable clinical outcome. Blood. 1997 Jun 1;89(11):4161-6
Krieger D, Moericke A, Oschlies I, Zimmermann M, Schrappe M, Reiter A, Burkhardt B. Frequency and clinical relevance of DNA microsatellite alterations of the CDKN2A/B, ATM and p53 gene loci: a comparison between pediatric precursor T-cell lymphoblastic lymphoma and T-cell lymphoblastic leukemia. Haematologica. 2010 Jan;95(1):158-62
Moorman AV, Ensor HM, Richards SM, Chilton L, Schwab C, Kinsey SE, Vora A, Mitchell CD, Harrison CJ. Prognostic effect of chromosomal abnormalities in childhood B-cell precursor acute lymphoblastic leukaemia: results from the UK Medical Research Council ALL97/99 randomised trial. Lancet Oncol. 2010 May;11(5):429-38
Mullighan CG. The molecular genetic makeup of acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program. 2012;2012:389-96
Nahi H, Hägglund H, Ahlgren T, Bernell P, Hardling M, Karlsson K, Lazarevic VLj, Linderholm M, Smedmyr B, Aström M, Hallböök H. An investigation into whether deletions in 9p reflect prognosis in adult precursor B-cell acute lymphoblastic leukemia: a multi-center study of 381 patients. Haematologica. 2008 Nov;93(11):1734-8
Roberts KG, Morin RD, Zhang J, Hirst M, Zhao Y, Su X, Chen SC, Payne-Turner D, Churchman ML, Harvey RC, Chen X, Kasap C, Yan C, Becksfort J, Finney RP, Teachey DT, Maude SL, Tse K, Moore R, Jones S, Mungall K, Birol I, Edmonson MN, Hu Y, Buetow KE, Chen IM, Carroll WL, Wei L, Ma J, Kleppe M, Levine RL, Garcia-Manero G, Larsen E, Shah NP, Devidas M, Reaman G, Smith M, Paugh SW, Evans WE, Grupp SA, Jeha S, Pui CH, Gerhard DS, Downing JR, Willman CL, Loh M, Hunger SP, Marra MA, Mullighan CG. Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia. Cancer Cell. 2012 Aug 14;22(2):153-66
Shahjahani M, Norozi F, Ahmadzadeh A, Shahrabi S, Tavakoli F, Asnafi AA, Saki N. The role of Pax5 in leukemia: diagnosis and prognosis significance. Med Oncol. 2015 Jan;32(1):360
Sulong S, Moorman AV, Irving JA, Strefford JC, Konn ZJ, Case MC, Minto L, Barber KE, Parker H, Wright SL, Stewart AR, Bailey S, Bown NP, Hall AG, Harrison CJ. A comprehensive analysis of the CDKN2A gene in childhood acute lymphoblastic leukemia reveals genomic deletion, copy number neutral loss of heterozygosity, and association with specific cytogenetic subgroups. Blood. 2009 Jan 1;113(1):100-7
Zhou M, Gu L, Yeager AM, Findley HW. Incidence and clinical significance of CDKN2/MTS1/P16ink4A and MTS2/P15ink4B gene deletions in childhood acute lymphoblastic leukemia. Pediatr Hematol Oncol. 1997 Mar-Apr;14(2):141-50
This article should be referenced as such:
Mohamed AN. del(9p) in Acute Lymphoblastic Leukemia. Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7):252-255.
Leukaemia Section Short Communication
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7) 256
Atlas of Genetics and Cytogenetics in Oncology and Haematology
INIST-CNRS OPEN ACCESS JOURNAL
der(X)t(X;8)(q28;q11.2) Tatiana Gindina
R.M. Gorbacheva Research Institute of Pediatric Oncology Hematology and Transplantation at First
Saint-Petersburg State Medical University named I.P.Pavlov, Saint-Petersburg, Russia /
Published in Atlas Database: September 2016
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0X08q28q11ID1641.html
Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68263/09-2016-t0X08q28q11ID1641.pdf DOI: 10.4267/2042/68263
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2017 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract Review on der(X)t(X;8)(q28;q11.2), with data on
clinics
Keywords
chromosome X; chromosome 8;
der(X)t(X;8)(q28;q11.2); acute lymphoblastic
leukemia
Identity
Partial GTG-banding karyotype of the der(X)t(X;8)(q28;q11.2).
Clinics and pathology
Disease
Acute lymphoblastic leukemia
Phenotype/cell stem origin
Leukemic cells were positive for CD34, CD10,
CD19, CD20, CD38.
Epidemiology
Extremely rare karyotypic event in ALL; both ALL
patients were males (aged 4 and 19 years).
Clinics
Among the characteristic laboratory features were a
low WBC at presentation. One of the two ALL
patients had a few reddish skin nodules 5-7 mm in
diameter, moderate hepatosplenomegaly. No patient
had a mediastinal mass or central nervous system
involvement at diagnosis, but one patient had CNS
extramedullary relapses, including post-transplant.
Case Leukemia Age/
Sex
WBC
109/L Karyotype Outcome References
1
B-
precursor
ALL
4/M 20 46,Y,der(X)t(X;8)(q28;q11.2),t(9;22)(q34;q11)
,t(8;14)(q11.2;q32),add(17)(p13)
CR; Relapsed after 23,5
mths
Kaleem et
al., 2000
2 Common
B ALL 19/M 17 46,Y,der(X)t(X;8)(q28;q11.2)
CR; Complex medullar and
CNS extramedullary
relapses after 10 mths and
13 mths; CR after BMT;
Isolated post-transplant
CNS relapse; died after 29
mths after diagnosis
Present
case, 2016
der(X)t(X;8)(q28;q11.2) Gindina T
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7) 257
Micro- and macrogenerations of lymphoblasts. Blasts had rounded nucleus and finely dispersed chromatin with well-contoured nucleoli. Iconography courtesy Valentina Kravtsova.
Cytology
Bone marrow are hypercellular with 54.4%
lymphoblasts of L1 or L2 morphology.
They were negative for myeloperoxidase, whereas
most of them positive for PAS stain. Erythropoiesis
and myelopoiesis were decreased. Erythropoiesis
had signs of megaloblastosis.
Megakaryocytopoiesis: hypolobular and polyploid
megakaryocytes.
Pathology
Histopathology of the skin nodules was remarkable
for interstitially located groups of small- and middle-
sized lymphoid blast-like cells, which were positive
for TdT, PAX-5, CD20, CD10, negative for T-cell
and myeloid markers and had a very high
proliferation rate (Ki-67 index above 90 %). myc
oncogene product was additionally assessed with
immunohistochemistry (clone Y69). Over 90% of
blast cells in the skin appeared to be positive for myc,
although staining pattern was markedly
heterogeneous. The brain tissue (at post-transplant
relapse) contained a dense cellular infiltrate
composed of middle-sized PAS-positive blasts with
oval or round nuclei, containing 2-3 small nucleoli.
Tumor cells were uniformly positive for TdT, CD19,
PAX-5, and CD79a and had a very high Ki-67
proliferation index. myc oncogene product was
demonstrated in over 85% of cells with
heterogeneous staining pattern, compatible with
indirect myc up-regulation.
Treatment
Complete therapeutic data are available for one of
the two ALL cases: treatment was started according
to ALL-2009 protocol, containing Daunorubicin,
Vincristine, and L-asparaginase. CNS prophylaxis
therapy consisted of triple intrathecal treatments,
whereas cranial irradiation was not used. The patient
received allogeneic HSCT; conditioning regimen
consisted of Melphalan and Fludarabine.
Prognosis
The risk associated with der(X)t(X;8)(q28;q11.2) is
not well determined due to low number of cases.
Cytogenetics
Cytogenetics morphological
Isolated derivative chromosome X was
demonstrated in one ALL case (present case, 2016);
in second one, the derivative chromosome X was
combined with other recurrent chromosomal
abnormalities (Kaleem et al, 2000).
Probes
Whole chromosome painting (WCP X, WCP8),
mBAND 8 (Metasystems, Germany).
Additional anomalies
Found in association with t(9;22)(q34;q11),
t(8;14)(q11.2;q32) and add(17)(p13) in one ALL
case (Kaleem et al,2000).
der(X)t(X;8)(q28;q11.2) Gindina T
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7) 258
GTG-banding showing the derivative X chromosome; FISH with whole painting probes showing two normal chromosomes 8 (green color) and the derivative der(X)t(X;8) (red and green colors). Multicolor banding of two normal chromosomes 8 and the
derivative X chromosome.
Genes involved and proteins
The unbalanced translocation
der(X)t(X;8)(q28;q11.2) results in a partial 8q
trisomy.
Result of the chromosomal anomaly
Hybrid gene
No specific gene or protein are described.
Fusion protein
Oncogenesis
The presence of partial 8q trisomy leads to gain of
genetic material and consequently to amplification
of genes possibly involved in the neoplastic process.
MYC is one of the genes located on 8q which may
be implicated in disease biology.
Immunohistochemical staining for MYC protein
showed positivity of >85% of leukemic cells,
although with markedly heterogeneous staining
pattern, compatible with indirect MYC up-
regulation. The latter, in turn, could increase
proliferative potential of leukemic cells as well as
their resistance to chemotherapy. In several studies,
trisomy 8 in ALL patients is considered to be
indicative of poor prognosis (Garipidou et al).
References Garipidou V, Yamada T, Prentice HG, Secker-Walker LM. Trisomy 8 in acute lymphoblastic leukemia (ALL): a case report and update of the literature. Leukemia. 1990 Oct;4(10):717-9
Kaleem Z, Shuster JJ, Carroll AJ, Borowitz MJ, Pullen DJ, Camitta BM, Zutter MM, Watson MS. Acute lymphoblastic leukemia with an unusual t(8;14)(q11.2;q32): a Pediatric Oncology Group Study. Leukemia. 2000 Feb;14(2):238-40
This article should be referenced as such:
Gindina T. der(X)t(X;8)(q28;q11.2). Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7):256-258.
Leukaemia Section Short Communication
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7) 259
Atlas of Genetics and Cytogenetics in Oncology and Haematology
INIST-CNRS OPEN ACCESS JOURNAL
t(1;9)(q24;q34) RCSD1/ABL1 Adriana Zamecnikova, Soad al Bahar
Kuwait Cancer Control Center, Department of Hematology, Laboratory of Cancer Genetics, Kuwait;
Published in Atlas Database: September 2016
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0109q24q34ID2109.html
Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68264/09-2016-t0109q24q34ID2109.pdf DOI: 10.4267/2042/68264
This article is an update of : De Braekeleer E, De Braekeleer M. t(1;9)(q24;q34). Atlas Genet Cytogenet Oncol Haematol 2008;12(6)
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2017 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract Review on t(1;9)(q24;q34) translocation, with data
on clinics, and the genes involved.
Keywords
chromosome 1; chromosome 9; ABL1; RCSD1; B-
cell acute lymphoblastic leukemia
Clinics and pathology Disease
B-cell precursor ALL with expression of CD79a+,
CD19+, CD10+, TdT (Mustjoki et al., 2009; Collette
et al., 2015 )
Epidemiology
12 cases with an ABL1 split by FISH and/or
RCSD1/ABL1 fusion, aged 5 to 40 years (median
age 15 years); male predominance (8 males and 4
females); among them 1 with ABL1-positive
biphenotypic ALL in which, however, the partner
gene has not been identifed.
Cytology
Hyperleukocytosis (WBC range at diagnosis 24 to
470 x 109, median 110 x 109); bone marrow blasts
ranging from 58 to 95%.
Prognosis Poor response to induction chemotherapy and in
addition to induction failure, a high risk of relapse
including patients after bone marrow transplantation.
B-ALL patients with the RCSD1/ABL1 fusion are
characterized by susceptibility to tyrosine kinase
inhibitor therapy
(imatinib, dasatinib, ponatinib) and may achieve
transient clinical effects as well as long time
remission (Table 1; Data from De Braekeleer et al.,
2013; Perwein et al., 2016) )
Cytogenetics
See Figure 1.
Genes involved and proteins
ABL1 (v-abl Abelson murine leukemia viral oncogene homolog 1)
Location
9q34.12
DNA/RNA
The ABL gene is aproximately 225 kb in size and is
expressed as a 7-kb mRNA transcript, with
alternatively spliced first exons, exons 1b and 1a,
respectively, spliced to the common exons 2-11.
Exon 1b is approximately 200 kb 5-prime of exon
1a.
Protein
The 145-kD ABL protein is classified as a
nonreceptor tyrosine kinase.
When the N-terminal region of the ABL protein is
encoded by exon 1a, the protein is believed to be
localized in the nucleus, while when encoded by
exon 1b, the resulting N-terminal glycine would be
myristylated and thus postulated to direct that
protein to the plasma membrane.
t(1;9)(q24;q34) RCSD1/ABL1 Zamecnikova A, al Bahar S
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7) 260
Sex/
Age Diagnosis
WBC
(x109/L)
PB/BM
blasts
(%)
Genetic testing results Therapy Survival
(months)
1 M/15 BAL 122 95/ NA 46,XY,t(1;9)(q23.3~q25;q34)
ABL1-rearranged (FISH) Chemotherapy 10 died
2* M/11 B-ALL 6 47/92
46,Y,add(X)(p22),t(1;9)(q24;q34)
ABL1-rearranged (FISH)
RCSD1-ABL1
Chemotherapy, BMT,
relapsed 2 years after
the initial treatment
97
3 40/M B-ALL 24 34/80 46,XY,t(1;9)(q24;q34)
RCSD1-ABL1
Chemotherapy +
dasatinib, BMT
Chemotherapy +
dasatinib/ imatinib at
relapse
66
4 F/18 B-ALL 110 87/ 92
t(1;9)(q24;q34)
ABL1-rearranged (FISH)
RCSD1-ABL1
NA NA
5 F/15 B-ALL 348 NA/NA 46,XX,t(1;9)(q24;q34)
RCSD1-ABL1
Chemotherapy, BMT
at 4, 35 and 84 months
following relapse.
84 died
6 M/31 B-ALL 146 90/NA
46,XY,t(1;9)(q23;q34),inv(2)(p21q
33)
Developed:
45,XY,t(1;9),inv(2),t(5;16)(q33;q2
4), dic(18;20)(p11;q11) and
46,XY,t(1;9),inv(2),t(5;16),dic(18;2
0),der(19)t(17;19)(q21;p13),+21
RCSD1-ABL1
Chemotherapy,
transient clinical
effects with imatinib,
and dasatinib.
6.5 died
7 M/16 B-ALL 48 NA/ NA RCSD1-ABL1 identified by RNA-
sequence analysis NA NA
8 M/18 B-ALL 470 52/58 46,XY,t(1;9)(q24;q34)
RCSD1-ABL1
No compliance to
therapy 12+
9 M/6 B-ALL 108 NA/ NA
46,XY,t(1;9)(q23;q34)
ABL1-rearranged
RCSD1-ABL1
Chemotherapy +
imatinib, poor response
to chemotherapy
1
10 F/26 B-ALL 26 84/86 46,XX,t(1;9)(q24;q34)
RCSD1-ABL1
Chemotherapy
+dasatinib, BMT,
relapse
Chemotherapy
+ponatinib, BMT
Ponatinib
monotherapy, relapse
25 died
11 F/15 B-ALL 251 45/NA 46,XX,t(1;9)(q24;q34)
IKS deletion
Chemotherapy +
dasatinib BMT 8 died
12 M/15 B-ALL 69 71/95 46,XY,t(1;9)(q31?;q34)
RCSD1-ABL1
Chemotherapy +
imatinib 2 months after
relapse: sustained
clinical remission
163
Abbreviations: WBC., white blood cells; PB., peripheral blood; BM., bone marrow; M., male; F., female; ALL., acute lymphocytic leukemia; * at relapse; BMT., bone marrow transplantation.
1. Gonzales et al., 2004; 2. De Braekeleer et al., 2011; 3. Mustjoki et al., 2009; 4. Zamecnikova et al., 2010; De Braekeleer et al., 2013; 5. De Braekeleer et al., 2011; 6. Inokuchi et al., 2011; 7. Roberts et al., 2012; 8. De Braekeleer et al., 2013; 9. Roberts
et al., 2014; 10. Collette et al.,2015; 11. Kamran et al., 2015; 12. Perwein et al., 2016
t(1;9)(q24;q34) RCSD1/ABL1 Zamecnikova A, al Bahar S
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7) 261
Figure 1. Top - courtesy Adriana Zamecnikova and Soad al Bahar: (A) Partial G-banded karyotypes showing the t(1;9)(q24;q34) and fluorescence in situ hybridization with LSI BCR/ABL1 (Vysis/Abott, US) probe showing the split of the ABL1 signal (red). A: Dual-color FISH using RP11-83J21 (labeled in spectrum orange) and RP11-232M22 (labeled in spectrum green) showing two
fusion genes. FISH, fluorescence in situ hybridization. B: Probes. Bottom - courtesy Etienne De Braekeleer and Marc De Braekeleer: R-banded karyotype showing the t(1;9)(q24;q34) translocation. Dual-color FISH using RP11-83J21 (labeled in
spectrum orange). Probes and RP11-232M22 (labeled in spectrum green) showing two fusion genes. FISH, fluorescence in situ hybridization. LSI bcr/abl dual extra-signal (ES) color probe (Abbott, Rungis, France) and BAC Probes. RP11-83J21
(chromosome 9) and RP11-232M22, RP11-928F1, RP11-138P14, RP11-652E14, RP11-64D9 (chromosome 1). All the probes that were used to find the breakpoint on der(1).
RCSD1 (RCSD domain containing 1)
Location
1q24.2
DNA/RNA
Eyers et al. (2005) cloned for the first time the human
RCSD1, which they called CAPZIP. A 416-amino
acid protein was deduced and they calculated a
molecular mass of 44.5 kD. Northern blot analysis
resulted in a major 3.4-kb transcript and a minor 7-
kb transcript that is highly expressed in skeletal
muscle and weakly in cardiac muscle. CAPZIP is
detected in several lymphoid organs, including
spleen, thymus, peripheral blood leukocytes, lymph
node, and bone marrow.
Protein
Eyers et al. (2005) found many properties of rabbit
Capzip. It interacted specifically with the F-actin
capping protein CapZ. This protein was
phosphorylated by : MAPKAPK2 and SAPK3
(MAPK12), on ser108 by SAPK3 and SAPK4
(MAPK13) and on ser68, ser83, and ser216 by JNK1
alpha-1 (MAPK8) in vitro. This team also found that
stress induced by hyperosmotic shock and
anisomycin, a protein synthesis inhibitor, stimulated
the phosphorylation of CAPZIP in human cell lines
t(1;9)(q24;q34) RCSD1/ABL1 Zamecnikova A, al Bahar S
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7) 262
and induced the dissociation of CAPZIP from CAPZ
in Jurkat human T cells. This phenomenon may
regulate the ability of CapZ to remodel actin
filament.
Result of the chromosomal anomaly
Hybrid gene
Description
RCSD1/ABL1. In-frame fusions of first three exons
of RCSD1 to ABL1 exon 4 to 11 and alternatively
spliced RCSD1/ABL1 consisting of the first two
exons of RCSD1 fused to exon 4 of ABL1 lacking
RCSD1 exon 3 (Mustjoki et al., 2009).
Detection
FISH detection.
Fusion protein
Description
The RCSD1/ABL1 fusion gene encode the tyrosine
kinase domain of ABL1. The chimeric protein
contains part of the SH2 domain of ABL1, the SH1
domain (that has tyrosine kinase function), the 3
nuclear localization signal domains, the 3 DNA-
binding regions and the F-actin-binding domain.
Notably, unlike most of the previously described
chimeric genes involving ABL1 that fuse with exon
2 of ABL1 (containing ABL1 exons 2 and 3), the
RCSD1/ABL1 protein contains only a truncated
ABL1 protein starting from the exon 4-encoded
region, therefore retains only a part of the ABL SH2
domain (with tyrosine kinase function), predicting
its association with ALL rather than chronic myeloid
leukemia (Mustjoki et al., 2009; De Braekeleer et al.,
2013; Collette et al., 2015).
Oncogenesis
The RCSD1 gene, which codes a protein kinase
substrate, CapZIP (CapZ-interacting protein), is
found in immune cells, splenocytes and muscle. It is
possible that the interaction between CapZIP and
CapZ affects the cell ability to remodel actin
filament assembly. CapZIP is phosphorylated when
cells are exposed to various cellular stresses, which
activate the kinase cascade. The interaction between
CapZIP and CapZ would be lost when CapZIP is
phosphorylated. So, RCSD1 would be involved in
the remodeling of the actin cytoskeleton, which is an
important step in mitosis. The probable formation of
the ABL1-RCSD1 fusion gene could result in an
alteration of the cellular function by affecting the
cytoskeleton regulation, which could be an
important step in leukemogenesis.
References Collette Y, Prébet T, Goubard A, Adélaïde J, Castellano R,
Carbuccia N, Garnier S, Guille A, Arnoulet C, Charbonier A, Mozziconacci MJ, Birnbaum D, Chaffanet M, Vey N. Drug response profiling can predict response to ponatinib in a patient with t(1;9)(q24;q34)-associated B-cell acute lymphoblastic leukemia. Blood Cancer J. 2015 Mar 13;5:e292
De Braekeleer E, Douet-Guilbert N, Guardiola P, Rowe D, Mustjoki S, Zamecnikova A, Al Bahar S, Jaramillo G, Berthou C, Bown N, Porkka K, Ochoa C, De Braekeleer M. Acute lymphoblastic leukemia associated with RCSD1-ABL1 novel fusion gene has a distinct gene expression profile from BCR-ABL1 fusion. Leukemia. 2013 Jun;27(6):1422-4
Eyers CE, McNeill H, Knebel A, Morrice N, Arthur SJ, Cuenda A, Cohen P. The phosphorylation of CapZ-interacting protein (CapZIP) by stress-activated protein kinases triggers its dissociation from CapZ. Biochem J. 2005 Jul 1;389(Pt 1):127-35
González García JR, Bohlander SK, Gutiérrez Angulo M, Esparza Flores MA, Picos Cárdenas VJ, Meza Espinoza JP, Ayala Madrigal Mde L, Rivera H. A t(1;9)(q23.3 approximately q25;q34) affecting the ABL1 gene in a biphenotypic leukemia. Cancer Genet Cytogenet. 2004 Jul 1;152(1):81-3
Inokuchi K, Wakita S, Hirakawa T, Tamai H, Yokose N, Yamaguchi H, Dan K. RCSD1-ABL1-positive B lymphoblastic leukemia is sensitive to dexamethasone and tyrosine kinase inhibitors and rapidly evolves clonally by chromosomal translocations. Int J Hematol. 2011 Sep;94(3):255-260
Kamran S, Raca G, Nazir K. RCSD1-ABL1 Translocation Associated with IKZF1 Gene Deletion in B-Cell Acute Lymphoblastic Leukemia. Case Rep Hematol. 2015;2015:353247
Mustjoki S, Hernesniemi S, Rauhala A, Kähkönen M, Almqvist A, Lundán T, Porkka K. A novel dasatinib-sensitive RCSD1-ABL1 fusion transcript in chemotherapy-refractory adult pre-B lymphoblastic leukemia with t(1;9)(q24;q34). Haematologica. 2009 Oct;94(10):1469-71
Roberts KG, Li Y, Payne-Turner D, Harvey RC, Yang YL, Pei D, McCastlain K, Ding L, Lu C, Song G, Ma J, Becksfort J, Rusch M, Chen SC, Easton J, Cheng J, Boggs K, Santiago-Morales N, Iacobucci I, Fulton RS, Wen J, Valentine M, Cheng C, Paugh SW, Devidas M, Chen IM, Reshmi S, Smith A, Hedlund E, Gupta P, Nagahawatte P, Wu G, Chen X, Yergeau D, Vadodaria B, Mulder H, Winick NJ, Larsen EC, Carroll WL, Heerema NA, Carroll AJ, Grayson G, Tasian SK, Moore AS, Keller F, Frei-Jones M, Whitlock JA, Raetz EA, White DL, Hughes TP, Guidry Auvil JM, Smith MA, Marcucci G, Bloomfield CD, Mrózek K, Kohlschmidt J, Stock W, Kornblau SM, Konopleva M, Paietta E, Pui CH, Jeha S, Relling MV, Evans WE, Gerhard DS, Gastier-Foster JM, Mardis E, Wilson RK, Loh ML, Downing JR, Hunger SP, Willman CL, Zhang J, Mullighan CG. Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. N Engl J Med. 2014 Sep 11;371(11):1005-15
Zámečníkova A. Chromosomal translocation t(1;9)(q24;q34) in acute lymphoblastic leukemia patient involving the ABL1 gene. Leuk Res. 2011 Sep;35(9):e149-50
This article should be referenced as such:
Zamecnikova A, al Bahar S. t(1;9)(q24;q34) RCSD1/ABL1. Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7):259-262.
Leukaemia Section Short Communication
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7) 263
Atlas of Genetics and Cytogenetics in Oncology and Haematology
INIST-CNRS OPEN ACCESS JOURNAL
t(3;9)(p13;q34.1) FOXP1/ABL1 Julie Sanford Biggerstaff
Idaho Cytogenetics Diagnostic Laboratory, Boise, ID 83706/ [email protected]
Published in Atlas Database: September 2016
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0309p13q34ID1619.html
Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68265/09-2016-t0309p13q34ID1619.pdf DOI: 10.4267/2042/68265
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2017 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract
Review on t(3;9)(p13;q34.1) FOXP1/ABL1, with
data on clinics, and the genes involved.
Keywords
chromosome 3; chromosome 9; FOXP1; ABL1; B
Cell Acute Lymphoblastic Leukemia; Follicular
Lymphoma
Clinics and pathology
Disease
Pre-B Cell Acute Lymphoblastic
Leukemia/Lymphoma (ALL) and Follicular
Lymphoma (Ernst et al., 2011; Koduru et al., 1997).
Note
The FOXP1/ABL1 involvement was ascertained
only in the B-ALL case. t(3;9) was found in a sub-
clone and against the background of a complex
karyotype and TP53 gene mutation in the follicular
lymphoma case.
Phenotype/cell stem origin
Pre-B cell.
Epidemiology
1 ALL case reported to date: a 16 yo female patient,
and 1 follicular lymphoma case reported to date: a 52
yo male patient.
Cytology
High leukocytosis (>50,000 x 109/L) at diagnosis.
Treatment
For ALL: Standard COALL (German Cooperative
Study Group) protocol for high-risk ALL followed
by Allogeneic BMT; may be sensitive to treatment
with first or 2nd generation tyrosine kinase inhibitors.
Prognosis
Yet unknown; ALL patient was reported in
remission 9 years post diagnosis, but after paternal
origin haplo-identical BMT.
Cytogenetics
Probes
ABL1 should show split signal using the standard
DCDF BCR/ABL1 construct.
Genes involved and proteins
FOXP1 (Forkhead box P1)
Location
3p13
Note
Member of forkhead box (FOX) subfamily P;
transcription factor. These proteins play a role in
cell- and tissue-specific gene transcription
regulation.
DNA/RNA
Gene is 176,228 bp with 16 exons; transcribed from
the - strand ; coding region is 171,437 bp with 14
exons.
Protein
At least 12 protein isoforms produced; dimerizes
with FOXP2 and FOXP4 using the leucine-zipper
domain which is required for DNA binding
capability.
Protein locates to the nucleus.
Germinal mutations
t(3;9)(p13;q34.1) FOXP1/ABL1 Sanford Biggerstaff JA
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7) 264
Germline mutations of FOXP1 are associated with
autosomal dominant intellectual disability with
language impairment, with or without autistic
features (MIM phenotype 613670).
ABL1 (v-abl Abelson murine leukemia viral oncogene homolog 1)
Location
9q34.12
DNA/RNA
Expressed as either 6- or 7-Kb transcript.
Protein
Tyrosine kinase; located in either the nucleus
(shorter transcript) or cytoplasm (longer transcript)
depending on which splice variant is produced
(Chissoe et al., 1995).
Result of the chromosomal anomaly
Hybrid gene
Note
In the single patient characterized, the in-frame
fusion was confirmed between FOXP1 exon 19
(ENST00000318789) and ABL1 exon 4
(ENST00000318560) (Ernst et al., 2011).
Description
ABL1 exon 4 fused with FOXP1 alternative RNA
isoform (NM_032682).
Detection
RT-PCR
References Chissoe SL, Bodenteich A, Wang YF, Wang YP, Burian D, Clifton SW, Crabtree J, Freeman A, Iyer K, Jian L. Sequence and analysis of the human ABL gene, the BCR gene, and regions involved in the Philadelphia chromosomal translocation. Genomics. 1995 May 1;27(1):67-82
Ernst T, Score J, Deininger M, Hidalgo-Curtis C, Lackie P, Ershler WB, Goldman JM, Cross NC, Grand F. Identification of FOXP1 and SNX2 as novel ABL1 fusion partners in acute lymphoblastic leukaemia. Br J Haematol. 2011 Apr;153(1):43-6
Hamdan FF, Daoud H, Rochefort D, Piton A, Gauthier J, Langlois M, Foomani G, Dobrzeniecka S, Krebs MO, Joober R, Lafrenière RG, Lacaille JC, Mottron L, Drapeau P, Beauchamp MH, Phillips MS, Fombonne E, Rouleau GA, Michaud JL. De novo mutations in FOXP1 in cases with intellectual disability, autism, and language impairment. Am J Hum Genet. 2010 Nov 12;87(5):671-8
Koduru PR, Raju K, Vadmal V, Menezes G, Shah S, Susin M, Kolitz J, Broome JD. Correlation between mutation in P53, p53 expression, cytogenetics, histologic type, and survival in patients with B-cell non-Hodgkin's lymphoma. Blood. 1997 Nov 15;90(10):4078-91
This article should be referenced as such:
Sanford Biggerstaff JA. t(3;9)(p13;q34.1) FOXP1/ABL1. Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7):263-264.
Leukaemia Section Short Communication
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7) 265
Atlas of Genetics and Cytogenetics in Oncology and Haematology
INIST-CNRS OPEN ACCESS JOURNAL
t(1;22)(p36;q11) IGL/PRDM16 Jean-Loup Huret
Medical Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021
Poitiers, France. [email protected]
Published in Atlas Database: September 2016
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0122p36q11ID1674.html
Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68266/09-2016-t0122p36q11ID1674.pdf DOI: 10.4267/2042/68266
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2017 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract Review on t(1;22)(p36;q11) IGL/PRDM16
translocations, with data on clinics, and the genes
involved.
Keywords
chromosome 1; chromosome22; t(1;22)(p36;q11);
IGL; PRDM16
Clinics and pathology
Disease
Splenic marginal zone B-cell lymphoma.
Clinics
Only one case to date: a 68-years old male patient,
who died 38 months after diagnosis (Duhoux et al.,
2012).
Cytogenetics
Cytogenetics morphological
Accompanying abnormalities were: +12, +18 and
t(1;14)(p12;q32).
Genes involved and proteins
PRDM16 (PR domain containing 16)
Location
1p36.32
DNA/RNA
11 splice variants
Protein
1276 amino acids and smaller proteins. Contains a
N-term PR domain; 7 Zinc fingers, a proline-rich
domain, and 3 Zinc fingers in the C-term. Binds
DNA. Transcription activator; PRDM16 has an
intrinsic histone methyltransferase activity.
PRDM16 forms a transcriptional complex with
CEBPB. PRDM16 plays a downstream regulatory
role in mediating TGFB signaling (Bjork et al.,
2010). PRDM16 induces brown fat determination
and differentiation. PRDM16 is expressed
selectively in the earliest stem and progenitor
hematopoietic cells, and is required for the
maintenance of the hematopoietic stem cell pool
during development. PRDM16 is also required for
survival, cell-cycle regulation and self-renewal in
neural stem cells (Chuikov et al., 2010; Kajimura et
al., 2010; Aguilo et al., 2011; Chi and Cohen, 2016).
IGL (Immunoglobulin Lambda)
Location
22q11.22
Result of the chromosomal anomaly
Fusion protein
Oncogenesis
IGL may act as an enhancer of PRDM16.
References Aguilo F, Avagyan S, Labar A, Sevilla A, Lee DF, Kumar P,
Lemischka IR, Zhou BY, Snoeck HW. Prdm16 is a physiologic regulator of hematopoietic stem cells. Blood. 2011 May 12;117(19):5057-66
t(1;22)(p36;q11) IGL/PRDM16 Huret JL
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7) 266
Bjork BC, Turbe-Doan A, Prysak M, Herron BJ, Beier DR. Prdm16 is required for normal palatogenesis in mice. Hum Mol Genet. 2010 Mar 1;19(5):774-89
Chi J, Cohen P. The Multifaceted Roles of PRDM16: Adipose Biology and Beyond. Trends Endocrinol Metab. 2016 Jan;27(1):11-23
Chuikov S, Levi BP, Smith ML, Morrison SJ. Prdm16 promotes stem cell maintenance in multiple tissues, partly by regulating oxidative stress. Nat Cell Biol. 2010 Oct;12(10):999-1006
Duhoux FP, Ameye G, Montano-Almendras CP, Bahloula K, Mozziconacci MJ, Laibe S, Wlodarska I, Michaux L,
Talmant P, Richebourg S, Lippert E, Speleman F, Herens C, Struski S, Raynaud S, Auger N, Nadal N, Rack K,
Mugneret F, Tigaud I, Lafage M, Taviaux S, Roche-Lestienne C, Latinne D, Libouton JM, Demoulin JB, Poirel HA. PRDM16 (1p36) translocations define a distinct entity of myeloid malignancies with poor prognosis but may also occur in lymphoid malignancies. Br J Haematol. 2012 Jan;156(1):76-88
Kajimura S, Seale P, Kubota K, Lunsford E, Frangioni JV, Gygi SP, Spiegelman BM. Initiation of myoblast to brown fat switch by a PRDM16-C/EBP-beta transcriptional complex. Nature. 2009 Aug 27;460(7259):1154-8
This article should be referenced as such:
Huret JL. t(1;22)(p36;q11) IGL/PRDM16. Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7):265-266.
Leukaemia Section Short Communication
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7) 267
Atlas of Genetics and Cytogenetics in Oncology and Haematology
INIST-CNRS OPEN ACCESS JOURNAL
t(1;3)(p36;q21) RPN1/PRDM16 Jean-Loup Huret
Medical Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021
Poitiers, France. [email protected]
Published in Atlas Database: September 2016
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0103p36q21ID2048.html
Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68267/09-2016-t0103p36q21ID2048.pdf DOI: 10.4267/2042/68267
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2017 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract Review on t(1;3)(p36;q21) translocations, with data
on clinics, and the genes involved.
Keywords
chromosome 1; chromosome3; t(1;3)(p36;q21);
RPN1; PRDM16
Identity
A translocation t(1;3)(p36;q21), with the same
breakpoints but involving PSMD2 and PRDM16
probably does not exist: 1- PSMD2 sits in 3q27, while the breakpoint is in
3q21;
2- PSMD2, a protein of the proteasome, is mainly
known in PubMed by its alias: "RPN1", while the
true RPN1, a protein involved in N-glycosylation
and sitting in 3q21, is better known by its full name:
"Ribophorin I".
Hence the confusion, found in a number of papers of
the literature.
Clinics and pathology
Disease
Myelodysplastic syndromes and acute myeloid
leukaemias
Note
A t(1;3)(p36;q21) RPN1/PRDM16 was found in 35
cases (Mochizuki et al., 2000; Shimizu et al., 2000:
Xinh et al., 2003; Duhoux et al., 2012)
Phenotype/cell stem origin
There were 19 myeloproliferative/myelodysplastic
syndromes: 1 chronic myeloid leukemia (CML), 3
refractory anaemia with ring sideroblasts (RARS); 6
refractory anemia with excess blasts (RAEB,
RAEB2, RAEB-T), 6 chronic myelomonocytic
leukaemia (CMML) and 3 myelodysplastic
syndrome not otherwise specified (MDS-NOS); and
16, acute myeloid leukaemias; 7 apparently de novo
(AML- M1, M2, M4, M5a, M6 and NOS), and 9
therapy-related or secondary AML.
Clinics
Median age was 66 years (range 29-92). Sex ratio
was 21 male/14 female patients (3/5 male, 2/5
female).
Prognosis
Median survival in 29 patients was 13-15 months;
five patients died within a month after diagnosis,
while 2 patients were long survivors (65 months +
and 80 months+).
Cytogenetics
Cytogenetics morphological
The t(1;3)(p36;q21) was the sole abnormality in 26
of 35 cases, and accompanied with del(5q) at
diagnosis in 5 cases. In 2 additional cases, the del(5q)
occurred during course of the disease. There was one
del(13q) and one del(20q), markers and a complex
karyotype were found in two cases.
t(1;3)(p36;q21) RPN1/PRDM16 Huret JL
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7) 268
Genes involved and proteins
PRDM16 (PR domain containing 16)
Location
1p36.32
DNA/RNA
11 splice variants
Protein
1276 amino acids and smaller proteins. Contains a
N-term PR domain; 7 Zinc fingers, a proline-rich
domain, and 3 Zinc fingers in the C-term. Binds
DNA.
Transcription activator; PRDM16 has an intrinsic
histone methyltransferase activity.
PRDM16 forms a transcriptional complex with
CEBPB. PRDM16 plays a downstream regulatory
role in mediating TGFB signaling (Bjork et al.,
2010).
PRDM16 induces brown fat determination and
differentiation.
PRDM16 is expressed selectively in the earliest stem
and progenitor hematopoietic cells, and is required
for the maintenance of the hematopoietic stem cell
pool during development. PRDM16 is also required
for survival, cell-cycle regulation and self-renewal in
neural stem cells (Chuikov et al., 2010; Kajimura et
al., 2010; Aguilo et al., 2011; Chi and Cohen, 2016).
RPN1 (ribophorin I)
Location
3q21.3
Note
RPN1 (Ribophorin I) (3q21.3, starts at 128338813
and ends at 128369719 bp from pter) must not be
confused with PSMD2 (proteasome 26S subunit,
non-ATPase 2) (3q27.1; starts at 184018369 and
ends at 184026842 bp from pter). PSMD2 aliases
are: RPN1, P97, S2, TRAP2 (see above).
DNA/RNA
8 splice variants
Protein
607 amino acids. RPN1 comprised of a signal
peptide (aa 1-23).RPN1 (Ribophorin I) is an
endoplasmic reticulum transmembrane protein and a
subunit of the oligosaccharyltransferase (OST)
complex. RPN1 regulates the delivery of precursor
proteins to the OST complex by presenting them to
the catalytic core. RPN1 acts as a substrate-specific
facilitator of N-glycosylation It may function as a
chaperone that recognizes misfolded proteins, and
plays a role in protein quality control in association
with MLEC (malectin) (Wilson and High, 2007;
Wilson et al., 2008; Takeda et al., 2014).
Result of the chromosomal anomaly
Hybrid gene
Description
5' RPN1 translocated to 3' PRDM16. The breakpoint
in PRDM16 is located either in the ?rst intron, or 5'
of exon 1. Transcriptional activation of can occur in
some patients, and fusion transcripts have been
generated in other patients.
t(1;3)(p36;q21) RPN1/PRDM16 Huret JL
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7) 269
Fusion protein
Oncogenesis
The 5' flanking regions of the rat RPN1 gene
containes GC-rich elements and an octamer motif. It
could serve as an enhancer, to activate transcription
of PRDM16 (Mochizuki et al., 2000; Shimizu et al.,
2000). Overexpression of PRDM16 (Duhoux et al.,
2012).
References Aguilo F, Avagyan S, Labar A, Sevilla A, Lee DF, Kumar P, Lemischka IR, Zhou BY, Snoeck HW. Prdm16 is a physiologic regulator of hematopoietic stem cells. Blood. 2011 May 12;117(19):5057-66
Bjork BC, Turbe-Doan A, Prysak M, Herron BJ, Beier DR. Prdm16 is required for normal palatogenesis in mice. Hum Mol Genet. 2010 Mar 1;19(5):774-89
Chi J, Cohen P. The Multifaceted Roles of PRDM16: Adipose Biology and Beyond. Trends Endocrinol Metab. 2016 Jan;27(1):11-23
Chuikov S, Levi BP, Smith ML, Morrison SJ. Prdm16 promotes stem cell maintenance in multiple tissues, partly by regulating oxidative stress. Nat Cell Biol. 2010 Oct;12(10):999-1006
Duhoux FP, Ameye G, Montano-Almendras CP, Bahloula K, Mozziconacci MJ, Laibe S, Wlodarska I, Michaux L, Talmant P, Richebourg S, Lippert E, Speleman F, Herens C, Struski S, Raynaud S, Auger N, Nadal N, Rack K, Mugneret F, Tigaud I, Lafage M, Taviaux S, Roche-Lestienne C, Latinne D, Libouton JM, Demoulin JB, Poirel HA. PRDM16 (1p36) translocations define a distinct entity of myeloid malignancies with poor prognosis but may also occur in lymphoid malignancies. Br J Haematol. 2012 Jan;156(1):76-88
Kajimura S, Seale P, Kubota K, Lunsford E, Frangioni JV, Gygi SP, Spiegelman BM. Initiation of myoblast to brown fat switch by a PRDM16-C/EBP-beta transcriptional complex. Nature. 2009 Aug 27;460(7259):1154-8
Mochizuki N, Shimizu S, Nagasawa T, Tanaka H, Taniwaki M, Yokota J, Morishita K. A novel gene, MEL1, mapped to 1p36.3 is highly homologous to the MDS1/EVI1 gene and is transcriptionally activated in t(1;3)(p36;q21)-positive leukemia cells. Blood. 2000 Nov 1;96(9):3209-14
Shimizu S, Suzukawa K, Kodera T, Nagasawa T, Abe T, Taniwaki M, Yagasaki F, Tanaka H, Fujisawa S, Johansson B, Ahlgren T, Yokota J, Morishita K. Identification of breakpoint cluster regions at 1p36.3 and 3q21 in hematologic malignancies with t(1;3)(p36;q21). Genes Chromosomes Cancer. 2000 Mar;27(3):229-38
Takeda K, Qin SY, Matsumoto N, Yamamoto K. Association of malectin with ribophorin I is crucial for attenuation of misfolded glycoprotein secretion. Biochem Biophys Res Commun. 2014 Nov 21;454(3):436-40
Wilson CM, High S. Ribophorin I acts as a substrate-specific facilitator of N-glycosylation. J Cell Sci. 2007 Feb 15;120(Pt 4):648-57
Wilson CM, Roebuck Q, High S. Ribophorin I regulates substrate delivery to the oligosaccharyltransferase core. Proc Natl Acad Sci U S A. 2008 Jul 15;105(28):9534-9
Xinh PT, Tri NK, Nagao H, Nakazato H, Taketazu F, Fujisawa S, Yagasaki F, Chen YZ, Hayashi Y, Toyoda A, Hattori M, Sakaki Y, Tokunaga K, Sato Y. Breakpoints at 1p36.3 in three MDS/AML(M4) patients with t(1;3)(p36;q21) occur in the first intron and in the 5' region of MEL1. Genes Chromosomes Cancer. 2003 Mar;36(3):313-6
This article should be referenced as such:
Huret JL. t(1;3)(p36;q21) RPN1/PRDM16. Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7):267-269.
Leukaemia Section Short Communication
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7) 270
Atlas of Genetics and Cytogenetics in Oncology and Haematology
INIST-CNRS OPEN ACCESS JOURNAL
t(1;17)(p36;q21) WNT3 or NSF/PRDM16 Jean-Loup Huret
Medical Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021
Poitiers, France. [email protected]
Published in Atlas Database: September 2016
Online updated version : http://AtlasGeneticsOncology.org/Anomalies/t0117p36q21ID2061.html
Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68268/09-2016-t0117p36q21ID2061.pdf DOI: 10.4267/2042/68268
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2017 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract Review on t(1;17)(p36;q21) translocation, with data
on clinics, and the genes involved.
Keywords
chromosome 1; chromosome 17; t(1;17)(p36;q21);
PRDM16; WNT3; NSF
Clinics and pathology
Disease
Acute myeloid leukaemia.
Clinics
Only one case to date, a 5-year-old girl who
presented with acute myeloid leukaemia. She died 6
months after diagnosis (Duhoux et al., 2012).
Cytogenetics
Cytogenetics morphological
The t(1;17)(p36;q21) was the sole anomaly.
Genes involved and proteins PRDM16, on chromosome 1, was implicated in the
translocation. However, which gene on chromosome
17 is involved in the malignant process is unknown:
two genes are located in the vicinity of the 17q21
breakpoint: WNT3 (44839872 - 44896126 bp from
pter) and NSF (44668035 - 44834828 bp from pter).
WNT3 (17q21.31), 355 amino acids, is one of the 19
known Wnt proteins. They bind a frizzled (Fz)/low
density lipoprotein receptor related protein (LRP)
complex, activating the cytoplasmic protein
dishevelled ( DVL1, DVL2 or DVL3), and the b-
catenin Wnt/beta catenin signaling pathway is
activated (Thorstensen and Lothe, 2003).
NSF (17q21.31), 744 amino acids, is a hexameric
ATPase. NSF catalyzes the fusion of transport
vesicles. Vesicle fusion is driven by specific
associations of complementary SNARE proteins
(soluble NSF attachment protein receptor) residing
on the vesicle (v-SNAREs) and target (t-SNAREs)
membranes. This mechanism involves NSF and its
adaptor protein, NAPA. This rmechanism of vesicle
fusion include endoplasmic reticulum-Golgi
transport, intra-Golgi vesicle fusion, trafficking from
the trans-Golgi network to the plasma membrane,
neuromediator exocytosis, and synaptic vesicle
fusion (Naydenov and Ivanov, 2013).
PRDM16 (PR domain containing 16)
Location
1p36.32
DNA/RNA
11 splice variants
Protein
1276 amino acids and smaller proteins. Contains a
N-term PR domain; 7 Zinc fingers, a proline-rich
domain, and 3 Zinc fingers in the C-term. Binds
DNA. Transcription activator; PRDM16 has an
intrinsic histone methyltransferase activity.
PRDM16 forms a transcriptional complex with
CEBPB. PRDM16 plays a downstream regulatory
role in mediating TGFB signaling (Bjork et al.,
2010). PRDM16 induces brown fat determination
and differentiation. PRDM16 is expressed
selectively in the earliest stem and progenitor
hematopoietic cells, and is required for the
t(1;17)(p36;q21) WNT3 or NSF/PRDM16 Huret JL
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7) 271
maintenance of the hematopoietic stem cell pool
during development. PRDM16 is also required for
survival, cell-cycle regulation and self-renewal in
neural stem cells (Chuikov et al., 2010; Kajimura et
al., 2010; Aguilo et al., 2011; Chi and Cohen, 2016).
Result of the chromosomal anomaly
Fusion protein
Oncogenesis
PRDM16 was not overexpressed (Duhoux et al.,
2012)
References Aguilo F, Avagyan S, Labar A, Sevilla A, Lee DF, Kumar P, Lemischka IR, Zhou BY, Snoeck HW. Prdm16 is a physiologic regulator of hematopoietic stem cells. Blood. 2011 May 12;117(19):5057-66
Bjork BC, Turbe-Doan A, Prysak M, Herron BJ, Beier DR. Prdm16 is required for normal palatogenesis in mice. Hum Mol Genet. 2010 Mar 1;19(5):774-89
Chi J, Cohen P. The Multifaceted Roles of PRDM16: Adipose Biology and Beyond. Trends Endocrinol Metab.
2016 Jan;27(1):11-23
Chuikov S, Levi BP, Smith ML, Morrison SJ. Prdm16 promotes stem cell maintenance in multiple tissues, partly by regulating oxidative stress. Nat Cell Biol. 2010 Oct;12(10):999-1006
Duhoux FP, Ameye G, Montano-Almendras CP, Bahloula K, Mozziconacci MJ, Laibe S, Wlodarska I, Michaux L, Talmant P, Richebourg S, Lippert E, Speleman F, Herens C, Struski S, Raynaud S, Auger N, Nadal N, Rack K, Mugneret F, Tigaud I, Lafage M, Taviaux S, Roche-Lestienne C, Latinne D, Libouton JM, Demoulin JB, Poirel HA. PRDM16 (1p36) translocations define a distinct entity of myeloid malignancies with poor prognosis but may also occur in lymphoid malignancies. Br J Haematol. 2012 Jan;156(1):76-88
Kajimura S, Seale P, Kubota K, Lunsford E, Frangioni JV, Gygi SP, Spiegelman BM. Initiation of myoblast to brown fat switch by a PRDM16-C/EBP-beta transcriptional complex. Nature. 2009 Aug 27;460(7259):1154-8
Naydenov NG ; Ivanov AI.. NAPA (N-ethylmaleimide-sensitive factor attachment protein, alpha). Atlas Genet Cytogenet Oncol Haematol. 2014;18(5):301-305.
Thorstensen L; Lothe RA.. The WNT signaling pathway, its role in human solid tumors. Atlas Genet Cytogenet Oncol Haematol. 2003;7(2):144-159.
This article should be referenced as such:
Huret JL. t(1;17)(p36;q21) WNT3 or NSF/PRDM16. Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7):270-271.
Cancer Prone Disease Section Review
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7) 272
Atlas of Genetics and Cytogenetics in Oncology and Haematology
INIST-CNRS OPEN ACCESS JOURNAL
Fanconi anemia Filippo Rosselli
UMR8200 CNRS, Gustave Roussy Institute, Université Paris-Saclay - Université Paris-Sud;
Published in Atlas Database: April 2016Online updated version : http://AtlasGeneticsOncology.org/Kprones/FAID10001.html Printable original version : http://documents.irevues.inist.fr/bitstream/handle/2042/68269/04-2016-FAID10001.pdf DOI: 10.4267/2042/68269
This article is an update of : Huret JL. Fanconi anaemia. Atlas Genet Cytogenet Oncol Haematol 2002;6(4) Huret JL. Fanconi anaemia. Atlas Genet Cytogenet Oncol Haematol 1998;2(2)
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2017 Atlas of Genetics and Cytogenetics in Oncology and Haematology
Abstract Fanconi anemia (FA) is a rare human recessive
syndrome featuring bone marrow failure,
myelodysplasia, and predisposition to cancer as well
as chromosome fragility and hypersensitivity to
DNA interstrands crosslinking agents. FA was
described in 1927 by the Swiss pediatrician
Giuseppe Fanconi, which reported a first family with
three affected sibling presenting developmental
defects and anemia.
FA cells are hypersensitive, at both cellular and
chromosomal levels, to the exposure to DNA
interstrands crosslinking agents, like mitomycin C,
diepoxybutane, cis-platinum or photoactivated
psoralen.
The chromosomal response to DNA interstrands
crosslinks (ICLs)-inducing agents is so typical that
the observation of both the induced frequency of
chromosome aberrations and their type, i.e. tri- and
quadri-radials, is considered the best diagnostic
criteria for FA.
Indeed, looking simply at the clinical hallmarks of
the patients, it is difficult to distinguish FA patients
from several other bone marrow failure syndromes.
Alternatively, since the FA cells need more time to
pass through both G2 and S phases than normal cell,
the analysis by flow cytometry of the over
accumulation of the FA cells in G2 following
exposure to ICL-inducing agents could be a useful
approach for diagnosis.
More recently, molecular and biochemical
approaches looking at gene mutations, proteins
expression and/or post-translational modifications
are used to validate cytogenetics conclusions.
To date 19 different genes (FANC) have been
associated to FA.
The FANC proteins constitute a pathway which
essential function is to deal with replication stress
assuring the transmission of a stable genome from
one cell to the daughters and acting both during
replication, to cope with stalled replication forks, but
also in G2 and M phases, to resolve un-replicated or
not fully replicated regions before telophase.
For review: Duxin and Walter, 2015; Bogliolo and
Surralles, 2015; Walden and Deans, 2014; Soulier
2011; Lobitz and Velleuer, 2006.
Keywords
Fanconi anemia, DNA repair, Replication, Acute
Myeloid Leukemia, Bone Marrow Failure.
Identity Other names
Fanconi pancytopenia
Note
Nineteen genes currently involved (for which bi-
allelic inactivating mutations are retrieved in
affected individual): FANCA, FANCB, FANCC,
BRCA2 (FANCD1), FANCD2, FANCE, FANCF,
FANCG (XRCC9), FANCI, BRIP1
(BACH1/FANCJ) FANCL, FANCM, PALB2
(FANCN), RAD51C (FANCO), SLX4 (FANCP),
ERCC4 (FANCQ/XPF) RAD51 (FANCR), BRCA1
(FANCS), UBE2T (FANCT).
Fanconi anemia Rosselli F.
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7) 273
A: gaps; B: breaks; C: deletion; D: triradials; E: quadriradials; F: complex figures; G: dicentric. Giemsa staining - Jean Loup Huret.
Inheritance
Autosomal recessive and X-linked (for FANCB); the
estimated prevalence is 1 to 5 cases for million
people; with a heterozygous carrier frequency of
around 1/300 people.
Cytogenetics
Inborn conditions
Spontaneous elevated levels of chromatid and
chromosome gaps and breaks, presence of abnormal
figures, in particular triradials and quadriradials. Hypersensitivity to the clastogenic effects of DNA crosslinking agents, like mitomycin C, diepoxybutane or cis-Platin.
Cytogenetics of cancer
Clonal abnormalities were reported in MDS and
AML: in particular: -5/del(5q) and -7/del(7q) .
Other findings slowing of the cell cycle (G2/M transition, with
accumulating of cells in G2)
impaired oxygen metabolism
defective P53 induction
Genes involved and proteins
Note
To date 19 complementation groups have been
described (A to T). FANCA represents 60 to 70% of
the patients, FANCC and FANCG (10 to 15% each),
meaning that all the other are extremely rare (less
than 3% each).
In response to DNA damage and together with
several other partners involved in DNA damage
signaling and cell cycle checkpoint activation, the
FANC proteins work long a linear pathway to cope
with the replication stress induced by the presence of
DNA lesions and help in the replication rescue by
homologous recombination based mechanism.
Briefly, FANCA, FANCB, FANCC, FANCE,
FANCF, FANCG and FANCL (with other
companion proteins) assemble on FANCM and meet
UBE2T to monoubiquitinate FANCD2 and FANCI.
Following their monoubiquitination, the
FANCD2/FANCI heterodimer assembles into
subnuclear foci where in a yet undetermined manner
participates to and/or coordinates the elimination of
the lesions and the restart of the stalled replication
fork thanks to the action of the other component of
the FANC pathway, which include structure specific
endonucleases (XPF, SLX4) and homologous
recombination proteins (RAD51, BRCA1, BRCA2,
...)
The pathway, or some of its components, participate
also to transcription regulation, epigentics,
production/response to inflammatory and stress
induced cytokines and interferons.
FANCA (Fanconi anemia, complementation group A)
Location
16q24.3
Fanconi anemia Rosselli F.
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7) 274
Note
The gene spans 80kB and contains 43 exons.
FANCA is the most frequently mutated among the
19 known FANC genes: it accounts for more than
60% of the FA patients worldwide.
Alternative splice results in the production of several
transcripts variants encoding different protein
isoforms.
The most representative protein is a polypeptide of
1455-amino acids weighting approximatively 163
kDa.
Present in both cytoplasms and nucleus, the protein
possesses a nuclear localization signal but lacks of
other known regulatory motifs and any biochemical
function was ascribed to it.
FANCA participates to the nuclear FANCcore
complex that hosts the E3 ligase (FANCL) activity
that, in collaboration with the E2 UBE2T,
monoubiquitinates FANCD2 and FANCI in
response to DNA damage. FANCA interacts directly
with FANCG and FAAP20.
Mutations
FANCB (Fanconi anemia complementation group B)
Location
Xp22.2
Note
FANCB is constituted by 10 exons spanning 77kB.
Alternative splicing results in two transcript variants
encoding a same protein of 859-amino acids with a
MW of 98 kDa. Any biochemical function was
reported for the protein.
FANCB aggregates with FANCL and FAAP100 in a
sub-complex that participates to the FANCcore
complex to mediate FANCD2 and FANCI
monoubiquitination in response to DNA damage.
FANCB stabilizes FANCL and needs FANCA to
translocate into thAe nucleus. Mutations in FANCB
are associated to both Fanconi anemia and X linked
VACTERL with hydrocephalus syndromes.
FANCC (Fanconi anaemia complementation group C)
Location
9q22.32
Note
FANCC has been the first FANC gene to be cloned.
It contains 14 exons and codes an ORF of 1677 bp
which translation results in a protein of 558aa,
weighting about 63kDa. The protein, present in both
cytoplasm and nucleus, interacts with FANCE and
FANCF, a subgroup participating to the FANCcore
complex. Any direct biochemical function was
reported for FANCC.
BRCA2 (breast cancer 2, early onset)
Location
13q13.1
Note
The gene contains 27 exons, coding a mRNA which
translation results in a protein of 3418aa, weighting
about 385kDa. The protein is involved in the
homologous recombination process.
FANCD1/BRCA2 contains several repetitions of a
70 aa motif called the BRC motif that mediate
Fanconi anemia Rosselli F.
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7) 275
RAD51 interaction. Indeed, FANCD1/BRCA2 is the
cargo that target RAD51 to ssDNA stretches covered
by RPA at DBS. It interacts with several proteins
involved in DNA metabolism, including FANCD2,
FANCN/PALB2, POLH and some components of
the TREX-2 complex. FANCD1/BRCA2 inherited
mutations are associated to the recessive syndrome
Fanconi
anemia while carriers of one inactivated allele are at
risk for breast and ovarian cancer predisposition
following the somatic loss-of-function of the wild-
type allele.
FANCD2 (Fanconi anemia, complementation group D2)
Location
3p25.3
Note
The gene contains 44 exons. FANCD2 encodes a
1,451-amino acid nuclear protein. As several other
FANC proteins, FANCD2 had no known functional
domains. With its major partner, FANCI, FANCD2
is the target of the Ubiquitin-ligase activity of the the
FANCcore complex. In presence of DNA damage or
replication stress, FANCD2 is monoubiquitinated on
K561 and targeted to subnuclear foci where it
colocalize with several DNA repair proteins. It is
phosphorylated by both ATM and ATR. The protein
participate to both replication safeguard and
chromosome fragile sites integrity maintenance.
Interacts directly or indirectly with several proteins,
including, FANCI, FANCE. USP1, MEN1, BRCA1,
BRCA2, phosphorylated FANCG, FAN1 and
DCLRE1B/Apollo.
FANCE (Fanconi anemia, complementation group E)
Location
6p21.31
Note
The gene contains 10 exons. FANCE protein is
constituted by 536 amino-acids weighting
approximatively 59kDa. It contains two Nuclear
Localization Signal (NLS). FANCE forms with
FANCC and FANCF a FANCcore complex sub-
complex. It is required for FANCC nuclear
accumulation and connects the FANCcore complex
to FANCD2 allowing the FANCL/UBE2T-mediated
FANCD2 monoubiquitination. It is phosphorylated
by CHK1 in response to DNA damage. As several
other FANC proteins, FANCE had no known
biochemical functions.
FANCF (Fanconi anemia, complementation group F)
Location
11p14.3
Note
FANCF is an intron-less gene. The protein, long of
374aa, weights 42kDa. FANCF is predominantly
nuclear, where it interacts with FANCE and
FANCC, a subgroup participating to the FANCcore
complex. As a FANCcore complex participant,
FANCF is involved in FANCD2 and FANCI
monoubiquitination. FANCF had no known
biochemical functions.
FANCG (Fanconi anemia, complementation group G)
Location
9p13.3
Note
The gene codes at least two mRNA of 2.2 and 2.5 kb,
which translation results in a major proteins of 622
aa, weighting 68kDa.
It participates to the FANCcore complex and its
phosphorylation on serine 7 is mandatory for its
function inside the complex.
Nevertheless, as for several other FANC proteins
any biochemical function has been attributed to
FANCG. As for the other components of the
FANCcore complex, its presence inside the complex
is mandatory for FANCD2 and FANCI
monoubiquitination and targeting to subnuclear foci.
FANCI (Fanconi anemia complementation group I)
Location
15q26.1
Note
The gene contains 38 exons. The FANCI protein is
long of 1328aa, weights 50kDa and contains 3 NLS.
FANCI is phosphorylated by ATM/ATR and is
monoubiquitinated by the FANCcore complex on
the lys523. It is considered as a functional homolog
of FANCD2. The two proteins forms a heterodimer
that, following their DNA damage- or replication
stress -induced monoubiquitination, relocalizes to
subnuclear foci to optimally restore DNA and rescue
replication in a yet undetermined manner.
BACH1 (BTB domain and CNC homolog 1)
Location
21q21.3
Note
The gene encodes a protein of 1249aa with a
molecular mass de 141kDa. Memeber of the RecQ
DEAH helicase family, FANCJ interact with
BRCA1 participating to the DNA double-strand
breaks repair by homologous recombination.
Germline mutations in FANCJ are associated to
breast and ovarian cancer susceptibility. Biallelic
inheritance results in a Fanconi anemia-like
phenotype.
Fanconi anemia Rosselli F.
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7) 276
BRIP1 (BRCA1 interacting protein C-terminal helicase 1)
Location
17q23.2
Note
The gene encodes a protein of 1249aa with a
molecular mass de 141kDa. Member of the RecQ
DEAH helicase family, FANCJ interact with
BRCA1 participating to the DNA double-strand
breaks repair by homologous recombination.
Germline mutations in FANCJ are associated to
breast and ovarian cancer susceptibility. Biallelic
inheritance results in a Fanconi anemia-like
phenotype
FANCL (Fanconi anemia complementation group L)
Location
2p16.1
Note
It codes a proteins of 373 aa, weighting 43 kDa,
containing 3 putative WD40 motifs and a PHD zync
finger motif. The protein could be retrieved in both
cytoplasm and nucleus. FANCL is the catalytic
subunit of the FANCore complex. It has the E3
ubiquitin ligase activity necessary for FANCD2 and
FANCI monoubiquitination. It mediate ubiquitin
release from UBE2T and UBE2W.
FANCM (Fanconi anemia complementation group M)
Location
14q21.2
Note
It code for a protein of 2048aa. Contains an N-
terminal helicase domain ans possess the ability to
translocate on duplex DNA. It belongs to the DEAD
box helicase family. It is hyperphosphorylated by
ATR in response of DNA damage FANCM is
thought be the transporter of the FANCcore complex
along the DNA and, so, it participates de facto to
both FANCD2 and FANCI optimal
monoubiquitination.
PALB2 (partner and localizer of BRCA2)
Location
16p12.2
Note
FANCN contains 13 exons and encodes for a protein
of 1186 aa having a molecular mass of about
130kDa. The protein participates to homologous
recombination in collaboration with its major partner
BRCA2. It interacts also with BRCA1, RAD51,
RAD51C and POLH. Monoallelic PALB2 mutations
confer predisposition to breast and pancreatic
cancers. hereditary bi-allelic mutations in FANCN
result in Fanconi anemia.
RAD51C (RAD51 paralog C)
Location
17q22
Note
Member of the RAD51 gene family, involved in
homologous recombination repair of damaged DNA
and in meiotic recombination. RAD51C encodes a
major 1.3 kB mRNA translated in a protein of 376
aa, weighting approximatively 45kDa. It interact
with several DNA repair proteins, including RAD51
and PALB2.
It participates to several complexes with RAD51B,
RAD51D and XRCC2 or with XRCC3. The
monoallelic inheritance of RAD51C is associated to
breast and ovarian cancers predispostion. The
biallelic, recessive, inheritance of RAD51C
mutations result in a Fanconi anemia-like syndrome.
SLX4 (SLX4 structure-specific endonuclease subunit)
Location
16p13.3
Note
The protein is constituted by 1834 aa which weights
about 200kDa. Component of the SLX1-SLX4
structure-specific endonuclease, it is the docking
platform of a complex assembling two other
structure specific enducleases: XPF-ERCC1 and
MUS81-EME1.
SLX4 is also associated to MSH2/MSH3, the
telomere binding complex TRF2-RAP1 and the
kinase PLK1. FANCP is required DNA repair,
chromosome fragile sites maintenance and for
replication fork failure rescue.
ERCC4 (xeroderma pigmentosum, complementation group F)
Location
16p13.12
Note
The gene contains 11 exons spanning more than 28
kb. The gene encodes 3 mRNA of 2.4, 3.8 and 7 kb,
which translation results in a protein of 905 aa,
having a mass of about 110 kDa. The protein
interacts primarily with with ERCC1 making up the
ERCC1-XPF-5' structure specific endonuclease. The
protein also interacst with FANCP/SLX4. Biallelic
inactivating mutation in this gene have been
associated to Fanconi anemia, xeroderma
pigmentosum, cockayne syndrome and XFE
progeroid syndrome.
RAD51 (RAD51 recombinase)
Location
Fanconi anemia Rosselli F.
Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7) 277
15q15.1
Note
Belonging to the RAD51 family, this gene is encodes
several transcript variant, the major being a 1.8kb
mRNA which translation results in a protein of
339aa weighting 37kDa which plays a central role in
homologous recobination repair and in meiotic
recombination. It interacts with BRCA1, BRCA2,
RPA, and several other DNA repair proteins. The
only Fanconi anemia patient associated to RAD51
mutation bears a de novo mutation which created a
dominant-negative variant. Mutations in RAD51
have been also associated to breast cancer
suceptibility and to the congenital Mirror
Movements 2 syndrome.
BRCA1 (breast cancer 1, early onset)
Location
17q21.31
UBE2T (ubiquitin conjugating enzyme E2 T)
Location
1q32.1
Note
The gene contains 7 exons. Two transcript variants
encodes different protein isoforms, the major is a
protein of 197 amino acids weighting
approximatively 22kDa. UBE2T is an E2-
conjugating enzyme that collaborates with FANCL,
the E3 ubiquitin ligase hosted by the FANC core
complex, for the monoubiquitination of FANCD2
and FANCI. It interact with FANCL and BRCA1.
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This article should be referenced as such:
Rosselli F. Fanconi anemia. Atlas Genet Cytogenet Oncol Haematol. 2017; 21(7):272-278.
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