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

Downstream molecules  PI 3 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  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 :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:

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 kinase fusion 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 : 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– 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 :4769: Np Cross, A Reiter. Tyrosine kinase fusion genes in chronic myeloproliferative diseases. Nature 2002; 16: 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.