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PDGF receptor β and leukemia

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					PDGF receptor β and leukemia
Caleb Parker

Overview
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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?
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Platelet-derived growth factor Acts as ligand for α- and βreceptors
PDGF

PDGFR

Heldin CH, Otsman A, Ronnstrand L. Signal transduction via Platelet-derived growth factor receptors. Biochem Biophys Acta 1998; 1378: F79-113

What is PDGFRB?
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Receptor tyrosine kinase

Heldin CH, Otsman A, Ronnstrand L. Signal transduction via Platelet-derived growth factor receptors. Biochem Biophys Acta 1998; 1378: F79-113

Downstream molecules
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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. Biochem Biophys Acta 1998; 1378: F79-113

Important areas of expression
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Normally expressed in endothelial cells and fibroblasts
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Role in wound healing

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Expressed on Myeloid and Erythroid precursors in bone marrow Expressed by mature monocytes, megakaryocytes, and osteoblasts

PDGFRB KO Mice
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Die at or around birth
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Numerous hematological defects Kidney malformation

Hoch Renee V, Soriano Philippe, Roles of PDGF in Animal development. Development 2003 130:4769:4784

Chronic Myelomonocytic Leukemia
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Persistent, elevated monocyte count (monocytosis) Hypercellular bone marrow Progression into Acute Myeloid leukemia

PDGFRB and CMML
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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
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The Tel/PDGFRB is most common Phenotypic differences not discerned

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Np Cross, A Reiter. Tyrosine kinase fusion genes in chronic myeloproliferative diseases. Nature 2002; 16: 1207-1212

What is Tel?
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Member of ETS family of transcription factors Two key domains:
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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

HLH

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.

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
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Possible Therapies
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Transformation is dependent on functional PDGFRB domain
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Imantib inhibits phosphorylation of PDGFRB

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Transformation is dependent on oligomerization of Tel/PDGFRB
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May be able to interfere with ability to oligomerize

Summary
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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/plateletderived 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. 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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