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HAEMOPOIETIC CYTOKINES AND SIGNALLING PATHWAYSDenise Pegnall
AIM
Understanding of the regulation of haemopoiesis
Haemopoietic Stem Cell Transcription factors Cytokines / Growth factors involved in
Haemopoiesis Haemopoiesis of different lineages Cytokine mode of action Cytokine Receptors Signalling Pathways
HAEMOPOIESIS
Haemopoiesis starts with stem cell division One cell replaces the stem cell The other cell is committed to differentiation
Embryonic yolk sac Mesenchyme of the yolk sac
Endothelial cells & Haemopoietic Stem Cells Early committed progenitor cells express low
levels of transcription factors that may commit them to the discrete cell lineages
PU.1 commits to myeloid lineage GATA-1 essential for erythroid and
megakaryocytes differentiation
Postgraduate H
aematology 5th E
d. 2005HAEMOPOIETIC TRANSCRIPTION FACTORS
REGULATION Extrinsic,intrinsic or both? Extrinsic
Cell-Cell interaction Cytokines
Small protein released by cells Interactions between cells, behaviour of cells Interleukins, lymphokines, cell signal molecules, interferons
Stem Cell Factor / receptor c-kit Flt3 ligand / receptor Flt3 Intrinsic
SCL, Stem cell leukaemia haemopoietic transcription factor GATA-2 Both required for haemopoiesis in the yolk sac
HAEMOPOIETIC ORGANISATION
Haemopoietic growth factors, (cytokines) Colony stimulating factors (CSF’s) Interleukins (IL’s)
SCF, IL-3,IL-6 : HSC CFU-L & CFU-GEMM (Stem Cells)
Thrombopoiesis Formed from CFU-Meg by endomitotic replication Megakaryocytes polyploid, 64n DNA content 2000-7000 platelets in each Megakaryocyte
Erythropoiesis mediated by Epo Decreased RBC leads to hypoxia increased Epo
synthesis
HAEMOPOIETIC ORGANIZATION
Lymphopoiesis: Lymphoid cell differentiates to Mature antigen committed lymphocytes in primary
lymphoid organs T lymphs differentiate in thymus gland B lymphs differentiate in foetal liver & adult bone marrow
Antigen dependent proliferation in secondary lymphoid organs B &T lymphs mature in spleen, lymph nodes, mucosa
associated lymphoid tissue
Granulopoiesis / Monopoiesis IL-3 & GM-CSF :CFU-GEMM BFU-E, CFU-Meg, CFU-GMEo, CFU-Baso
CFU-E, CFU-GM, CFUEo: CFU-G & CFU-M
HIERARCHICAL ORGANIZATION OF HAEMOPOIESIS
Adapted from Postgraduate Haematology 5th Ed. 2005
IL-3 &GM-CSF
IL-3EP0IL-4GM-CSF
SCFIL-3IL-6
IL-1,IL-3,IL-6
IL-3EPOGM-CSF
IL-3GM-CSFTPO
IL-3IL-5GM-CSF
CFU- Baso
Basophils
IL-3
M-CSFG-CSF
Postgraduate H
aematology 5th E
d. 2005
HAEMOPOIETIC CYTOKINES & THEIR TARGET CELLS
CYTOKINES & GROWTH FACTORS
Soluble regulators of blood cell production Produced by several cell types in different
sites in the body Glycoproteins
anti-parallel α helices joined by loops & β-sheets
Some exist also in membrane bound forms Lack sequence responsible for release from the
cell Haemopoietic progenitors require multiple
cytokines for optimal growth & development
CYTOKINES
Six major types of cytokine chemokines, colony-stimulating factors,
interferons, interleukins, transforming growth factors, and tumour necrosis factors (TNF)
Modes of action Autocrine, on cells that produce them Paracrine, on cells in the immediate vacinity Endocrine, on cells at a distance
Act in synergy or antagonistically Have pleiotropic actions
CYTOKINE RESPONSES AND SIGNAL TRANSDUCTION
Haemopoietic cell responses include Survival, proliferation, differentiation Stimulation of mature cell function
Modulate haemopoietic responses by accessing target cell receptors
Bind to receptors on cell surface Activates signal transduction pathways Transmits a signal to the nucleus Stimulates the transcription of regulatory
genes
SIGNALLING PATHWAYS
Haemopoietic cell function regulated by cytokines through activation of signal transduction pathways
Relevant to cell proliferation & differentiation Janus Kinase(Jak)/ Signal transducers and
activators of transcription (STATS) Mitogen-activated protein (MAP) Kinase Phosphatidylinisitol (PI)3-Kinase
Postgraduate H
aematology 5th E
d. 2005
JAK /STAT PATHWAY
Postgraduate H
aematology 5th E
d. 2005
JAK /STAT PATHWAY
Postgraduate H
aematology 5th E
d. 2005
GENERALIZED DIAGRAM OF THE SIGNAL TRANSDUCTION PATHWAYS ACTIVATED BY CYTOKINES AND THEIR RECEPTORS IN HAEMOPOIETIC CELLS
CYTOKINES RECEPTORS
Haemopoietic receptor cytokine superfamily Share a common Trp-Ser-X-Trp-Ser motif (X= any amino acid)
Two main types Single chain
Intrinsic tyrosine kinase domains G-CSF, Epo
Heterodimers (2 or more subunits) GM-CSF IL-3
Postgraduate H
aematology 5th E
d 2005
CYTOKINE RECEPTOR SUPERFAMILY
BASIC IMMUNOPHENOTYPES OF HAEMOPOIETIC STEM CELLS
POSITIVE NEGATIVE
CD34 CD33
Thy-1 CD38
AC133 Lineage Markers
c-Kit HLA-DR
Postgraduate haem
atology 5th Ed. 2005
E2F
Retinoblastoma