PDGF receptor β and leukemia
Caleb Parker
Overview
What is PDGFRB? What role does PDGFRB play in the
cell? What is CMML? What is Tel/PDGFRB? What is the connection between
CMML and Tel/PDGFRB? What are the potential therapies for
CMML?
What is PDGF?
Platelet-derived growth factor Acts as ligand for α- and β-receptors
PDGF
PDGFR
Heldin CH, Otsman A, Ronnstrand L. Signal transduction via Platelet-derived growth factor receptors. BiochemBiophys Acta 1998; 1378: F79-113
What is PDGFRB?
Receptor tyrosine kinase
Heldin CH, Otsman A, Ronnstrand L. Signal transduction via Platelet-derived growth factor receptors. BiochemBiophys Acta 1998; 1378: F79-113
Downstream molecules
PI3 Kinase
PLC-γ Grb2/Sos1 Src Fer Stat SHP-2 GAP
Cellular roles of PDGFRB
Heldin CH, Otsman A, Ronnstrand L. Signal transduction via Platelet-derived growth factor receptors. BiochemBiophys Acta 1998; 1378: F79-113
Important areas of expression
Normally expressed in endothelial cells and fibroblasts Role in wound healing
Expressed on Myeloid and Erythroid precursors in bone marrow
Expressed by mature monocytes, megakaryocytes, and osteoblasts
PDGFRB KO Mice
Die at or around birth Numerous hematological defects Kidney malformation
Hoch Renee V, Soriano Philippe, Roles of PDGF in Animal development. Development 2003 130:4769:4784
Chronic Myelomonocytic Leukemia
Persistent, elevated monocyte count (monocytosis)
Hypercellular bone marrow Progression into Acute Myeloid
leukemia
PDGFRB and CMML
In late 1980s, a chromosome translocation t(5;12)(q31q33;p12) was associated with patients with CMML
Translocation results in a fusion protein
Other unique translocations have been discovered
PDGFRB has many partner genes
The Tel/PDGFRB is most common
Phenotypic differences not discerned
Np Cross, A Reiter. Tyrosine kinase fusion genes in chronic myeloproliferative diseases. Nature 2002; 16: 1207-1212
What is Tel?
Member of ETS family of transcription factors
Two key domains: Helix-Loop-Helix (HLH) domain DNA binding domain
Carroll M, Tomasson MH, Barker GF, Golub TR, and Gilliland DG (1996) The TEL/platelet-derived growth factor beta receptor (PDGF beta R) fusion in chronic myelomonocytic leukemia is a transforming protein that self-associates and activates PDGF beta Leukemia R kinase-dependent signaling pathways. Proc Natl Acad Sci USA 1996; 93: 14845–14850.
Fusion protein Tel/PDGFRB
Wilbanks AM, Mahajan S, Frank DA, Druker BJ, Gilliland DG, Carroll M. TEL/PDGFbetaR fusion protein activates STAT1 and STAT5: a common mechanism for transformation by tyrosine kinasefusion proteins. Exp Hematol 2000; 28: 584–593.
HLH
What causes transformation?
Transformation is dependent on Tel HLH domain and PDGFRB kinase activity
HLH is shown to mediate dimerization
Consistent with model that T/P dimerizes via HLH domain and leads to consituitve activation
Possible Therapies
Transformation is dependent on functional PDGFRB domain Imantib inhibits phosphorylation of
PDGFRB Transformation is dependent on
oligomerization of Tel/PDGFRB May be able to interfere with ability to
oligomerize
Summary
PDGFRB is a RTK involved in the maintenance of the hematopoetic system
CMML is a type of leukemia marked by monocytosis
A fusion protein, Tel/PDGFRB, is associated with CMML
Therapies for CMML are developed based on the knowledge of how Tel/PDGFRB transforms a cell
Resources
Betscholtz christer, Role of Platelet-derived Growth factor in mouse development. Int. J. Dev. Biol. 1995 39:817-825
Carroll M, Tomasson MH, Barker GF, Golub TR, and Gilliland DG (1996) The TEL/platelet-derived growth factor beta receptor (PDGF beta R) fusion in chronic myelomonocytic leukemia is a transforming protein that self-associates and activates PDGF betaLeukemia R kinase-dependent signaling pathways. Proc Natl Acad Sci USA1996; 93: 14845–14850.
Golub TR, Barker GF, Lovett M, Gilliland DG. Fusion of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation. Cell 1994; 77: 307–316.
Hoch Renee V, Soriano Philippe, Roles of PDGF in Animal development. Development 2003 130:4769:4784
http://www.leukemia-lymphoma.org/all_page.adp?item_id=557237
Np Cross, A Reiter. Tyrosine kinase fusion genes in chronic myeloproliferative diseases. Nature 2002; 16: 1207-1212
Wilbanks AM, Mahajan S, Frank DA, Druker BJ, Gilliland DG, Carroll M. TEL/PDGFbetaR fusion protein activates STAT1 and STAT5: a common mechanism for transformation by tyrosine kinase fusion proteins. Exp Hematol 2000; 28: 584–593.
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