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PDGF receptor β and leukemia

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

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PDGF receptor β and leukemia

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  1. PDGF receptor β and leukemia Caleb Parker

  2. 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?

  3. 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

  4. 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

  5. Downstream molecules • PI3 Kinase • PLC-γ • Grb2/Sos1 • Src • Fer • Stat • SHP-2 • GAP

  6. 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

  7. 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

  8. 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

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

  10. 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

  11. 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

  12. 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.

  13. 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.

  14. 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

  15. 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

  16. 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

  17. 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 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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