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PDGF- β Receptor

The PDGF-β receptor (PDGFR-β) is a receptor tyrosine kinase activated by PDGF ligand dimers, vital for processes such as wound healing, angiogenesis, and hematopoietic stem cell differentiation. Its dysfunction leads to chronic myelomonocytic leukemia (CMML), characterized by an increase in monocytes and myelocytes. PDGFR-β can become oncogenic through chromosomal translocations, notably the TEL-PDGF-βR fusion. Treatment options include tyrosine kinase inhibitors and monoclonal antibodies, offering hope despite currently poor outcomes. The receptor's key effectors are PI3K and PLCγ.

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PDGF- β Receptor

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  1. PDGF-β Receptor Chris Halloran 03.04.2004 Baker, http://www.bcm.tmc.edu/medicine/hema-onco/lectures/mds/sld017.htm.

  2. PDGF-β Receptor Function • Receptor Tyrosine Kinase • Activated by PDGF ligand dimers. Lodish et al. Fig. 20-21

  3. PDGFR Ligands http://www.licr.org/07_spot/PDGF.htm

  4. http://bind.ca/tutorials/pdgfr_tut/pdgfr_breakdown.html

  5. Cytological Effectors • 13 phospho-Y residues • Phosphatidylinositol 3’ kinase (PI3K) & Phospholipase C-γ (PLCγ) are key effectors Tallquist, et al., PLOS Biology (2003), 288-99.

  6. Activated after wounding ~ stimulates vascular growth (angiogenesis) Erythroid & myeloid precursor cells (hematopoeitic stem cells) - Monocyte differentiation - Macrophage activation The Biology of PDGF-βR Cross & Reiter, Leukemia (2002), 1207-12.

  7. Knockouts • Mouse KO’s for PDGF-A & B and their receptors • Disappointing results • for PDGF-βR KO’s…

  8. PDGF-βR KO Phenotype Perinatal Death! Vascular Weaknesses & Cardiac Hypertrophy! Misdeveloped Kidneys! WHY??? Redundancy in the PDGFR superfamily. Hoch and Soriano, Development 120 (30), 4769-84.

  9. PDGF-βR, the Oncogene • Disease: Chronic Myelomonocytic Leukemia (CMML) - myeloproliferative disorder (MPD) • Constitutive activation by chromosomal translocation t(5;12) - novel gene product TEL-PDGF-βR - TEL: transcription factor Sjöblom, et al., Oncogene (1999) 18, 7055-62. http://www.infobiogen.fr/services/chromcancer/Genes/ETV6ID38.html

  10. TEL Why does this help PDGF-βR become oncogenic? • Helix-turn-helix domain near N-terminus - Self binds - Important for angiogenesis & bone marrow hematopoiesis Chackrabarti, et al., Proc Natl Acad Sci 1999, 96 (13): 7467–72.

  11. What happens in CMML? • CMML is late onset (~70 yrs), male dominance, median survival ~20 months • General symptoms: fatigue, shortness of breath, enlarged spleen and lymph glands, bruising, & abnormal bleeding • Anemia & increase in monocytes and myelocytes • Marrow rich in developing monocytes and myelocytes, however http://www.leukemia-lymphoma.org/all_mat_toc.adp?item_id=69974&cat_id=1215

  12. Treatment Options • Tyrosine kinase inhibitor (Gleevec—Phase II) plus allogenic transplant (stem cells) shown effective • Topoisomerase I inhibitor (Topotecan) ~allowing p53 mediated apoptosis • Monoclonal AB therapy

  13. In Conclusion… • PDGF-βR is an RTK. • Its major effectors are PI3K and PLCγ. • PDGF-βR is important for wound healing, blood cell differentiation, & vascular development. • PDGF-βR is often mutated in Chronic Myelomonocytic Leukemia because of a translocation. - PDGF-βR is an oncogene. - CMML treatment is currently bleak but hope exists.

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