BIOL 445 – CANCER BIOLOGY PRESENTATION KARRA C. PASONS BIOL 445 – CANCER BIOLOGY PRESENTATION

PDGFRβ Platelet Derived Growth Factor Receptor Beta And its role in Leukemia http://old.sinobiological.com/Platelet-derived-growth-factor/Structures-of-a-platelet-derived-growth-factor.jpg

PDGFRβ is a receptor tyrosine kinases (RTK) that receives PDGF signals Binding of PDGF to its receptors leads to activation of the RTK which leads to subsequent launching of cytoplasmic signal transduction pathways Induces migration, proliferation, and differentiation in PDGF-responsive cell types. https://www.withfriendship.com/images/i/44179/the-activation-of-pkc-is.jpg

There are multiple PDGF ligands and receptors and dimer ligands dimerize receptors PDGF consist of disulfide bonded dimers of two polypeptide chains Dimerization of both ligands and receptors necessary for function Only PDGFA and PDGFB are capable of forming functional heterodimer ligands (Hoch – 2003)

PDGFβ mutants die Perinatally with defects in blood cells and the kidney Perinatal Death – were anemic, thrombocytopenic and had defects in formation of kidney Glomeruli Localization in mesenchymal cells (Soriano – 1994) (Soriano – 1994)

The transcription factor c-Myb is a Downstream Target of PDGFβ c-Myb protein expression in VSMC (vascular smooth muscle cells) shows increased after PDGF-BB treatment (activates PDGFRα and PDGFRβ). PDGF signaling stimulates and maintains c-Myb expression in VSMCs. (Chen – 2007) c-Myb concentration after treatment with PDGF BB ligand

C-Myb inhibits apoptosis of vascular smooth muscle cells Truncated PDGFRα induces apoptosis c-Myb overrides the apoptotic effects of truncated PDGFRα Overexpression of c-Myb inhibits apoptosis of VSMCs induced by truncated PDGFRα. Inhibition of c-Myb function induces apoptosis in VSMCs treated with PDGF. c-Myb is a downstream target of PDGF signaling that maintains VSMC survival. (Chen – 2007)

Chronic Myelomonocytic Leukemia CMML is a myelodyplastic syndrome characterized by clonal myeloid proliferation and progression into AML (acute myelogenous leukemia) 4 in a million people a year in USA 9 out of 10 people are diagnoses at 60 years or older http://www.pubcan.org/images/lym4/thumb/lym4-03a.jpg

CMML is associated with Chromosome Translocation t(5;12)(q33;p13) fusing tel and PDGFRβ Large arrow represents fused chromosome (Golub - 1994) (Golub - 1994)

The HLH Domain Of Tel Is Fused To PDGFR And Dimerizes Receptor Without Ligand! tel is a member of the ets gene family The ets gene family are DNA binding proteins that recognize the core motif C/A GGA A/T and are thought to act as transcription activators. HLH – helix loop helix HLH domain is dimeric, with one helix containing basic amino acid residues that facilitate DNA binding Tel HLH Domain facilitates ligand Independent dimerization Activation of pathway with out extracellular signaling CMML patients phenotypically similar to CML with c-Abl activated http://www.uni-salzburg.at/uploads/RTEmagicP_DNA_transcription.jpg

Gleevec (Imatinib) is a small molecule tyrosine kinase inhibitor that inhibits PDGFR Blocks kinase domain Binds to ATP binding site when in inactive state New mutations in active site that inhibit Imatinib binding http://onlinelibrary.wiley.com/store/10.1111/febs.12163/asset/image_m/febs12163-toc-0001-m.png?v=1&s=756f1b64ec5cb0ffc3ae3817777e1fc0e3080bf0

AMN107 is another tyrosine kinase inhibitor developed to help deal with Gleevec resistance Significantly lower WBC count after 7 days in AMN107 treated mice P<0.05 Developed due to imatinib resistance mutations Interferes with Kinase activity by binding the ATP binding site in when in an inactive state. Reduces autophosphorylation (Stover – 2005)

Summary PDGFRβ is a receptor tyrosine kinase found in mesenchyme cells (eg. VSMC and myeloid cells) Causes activation of downstream transcription activators such as c-myb tel-PDGFRβ translocation causes CMML by leading to constitutively active PDGFRβ tel-PDGFRβ allows cells to escape cellular regulatory pathways such as apoptosis Gleevec and AMN107 are small molecule inhibitors of PDGFRβ

References American Cancer Society, “Leukemia: Chronic Myelomonocytic” (2012 Mar. 21); Retrieved from http://www.cancer.org/cancer/leukemia-chronicmyelomonocyticcmml/detailedguide/leukemia-chronic-myelomonocytic-what-is-it Apperley, Jane F., et. al, “Response to imatinib mesylate in patients with chronic myeloproliferative diseases with rearrangements of the platelet-derived growth factor receptor beta”, N Engl Med, Vol. 347 No. 7; (2002 Aug. 15) Chen, Yitan, “The c-Myb functions as a downstream target of PDGF-mediated survival signal in vascular smooth muscle cells” Biochemical and Biophysical Research Communications, Vol. 360, Issue 2,, Pg. 433-436 (2007, Aug. 24) Cross, NCP and Reiter, A., “Tyrosine kinase fusion genes in chronic myeloproliferative diseases” Leukemia 16, 1207-1212 (2002) Golub, Todd R., ”Fusion of PDGF Receptor β to a Novel ets-like Gene, tel in Chronic Myelomonocytic Leukemia with t(5;12) Chromosomal Translocation” Cell, Vol. 77, 307-316. (1994, April 22) Hoch, Renee V. And Soriano, Phillippe, ”Roles of PDGF in animal development”, Develpment 130, 4769-4784; (2003) Soriano, Phillippe, “Abnormal kidney development and hematological disorders in PDGFβ-receptor mutant mice. Genes and Development. ;(1996) Stover, Elizabeth, H., et. al, “The small molecule tyrosine kinase inhibitor AMN107 inhibits TEL-PDGFRβ AND FIP1L1-PDGFRα in vitro and in vivo” Blood Vol. 106 No. 9; (2005 Nov. 1)