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Page 1: 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?

PDGF receptor β and leukemia

Caleb Parker

Page 2: 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?

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?

Page 3: 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 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

Page 4: 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 PDGFRB?

Receptor tyrosine kinase

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

Page 5: 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?

Downstream molecules

PI3 Kinase

PLC-γ Grb2/Sos1 Src Fer Stat SHP-2 GAP

Page 6: 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?

Cellular roles of PDGFRB

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

Page 7: 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?

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

Page 8: 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?

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

Page 9: 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?

Chronic Myelomonocytic Leukemia

Persistent, elevated monocyte count (monocytosis)

Hypercellular bone marrow Progression into Acute Myeloid

leukemia

Page 10: 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?

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

Page 11: 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?

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

Page 12: 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 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.

Page 13: 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?

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

Page 14: 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 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

Page 15: 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?

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

Page 16: 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?

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

Page 17: 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?

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.