PDGF receptor ² and leukemia Caleb Parker. Overview ï‚ What is PDGFRB? ï‚...

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Transcript of PDGF receptor ² and leukemia Caleb Parker. Overview ï‚ What is PDGFRB? ï‚...

  • PDGF receptor and leukemiaCaleb Parker

  • OverviewWhat 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 factorActs as ligand for - and -receptorsPDGFPDGFRHeldin CH, Otsman A, Ronnstrand L. Signal transduction via Platelet-derived growth factor receptors. BiochemBiophys 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. BiochemBiophys Acta 1998; 1378: F79-113

  • Downstream moleculesPI3 KinasePLC-Grb2/Sos1SrcFer StatSHP-2GAP

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

  • Important areas of expressionNormally expressed in endothelial cells and fibroblastsRole in wound healingExpressed on Myeloid and Erythroid precursors in bone marrowExpressed by mature monocytes, megakaryocytes, and osteoblasts

  • PDGFRB KO MiceDie at or around birthNumerous hematological defectsKidney malformation

    Hoch Renee V, Soriano Philippe, Roles of PDGF in Animal development. Development 2003 130:4769:4784

  • Chronic Myelomonocytic LeukemiaPersistent, elevated monocyte count (monocytosis)Hypercellular bone marrowProgression into Acute Myeloid leukemia

  • PDGFRB and CMMLIn late 1980s, a chromosome translocation t(5;12)(q31q33;p12) was associated with patients with CMMLTranslocation results in a fusion proteinOther unique translocations have been discovered

  • PDGFRB has many partner genesThe Tel/PDGFRB is most common

    Phenotypic differences not discernedNp Cross, A Reiter. Tyrosine kinase fusion genes in chronic myeloproliferative diseases. Nature 2002; 16: 1207-1212

  • What is Tel?Member of ETS family of transcription factorsTwo key domains:Helix-Loop-Helix (HLH) domainDNA binding domainCarroll 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: 1484514850.

  • Fusion protein Tel/PDGFRBWilbanks 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: 584593.

    HLH

  • What causes transformation?Transformation is dependent on Tel HLH domain and PDGFRB kinase activityHLH is shown to mediate dimerizationConsistent with model that T/P dimerizes via HLH domain and leads to consituitve activation

  • Possible TherapiesTransformation is dependent on functional PDGFRB domainImantib inhibits phosphorylation of PDGFRBTransformation is dependent on oligomerization of Tel/PDGFRBMay be able to interfere with ability to oligomerize

  • SummaryPDGFRB is a RTK involved in the maintenance of the hematopoetic systemCMML is a type of leukemia marked by monocytosisA fusion protein, Tel/PDGFRB, is associated with CMMLTherapies for CMML are developed based on the knowledge of how Tel/PDGFRB transforms a cell

  • ResourcesBetscholtz 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: 1484514850.

    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: 307316.

    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: 584593.

    ***PDGF is a dimeric molecule of a and b chains. These chains can combine to form three isoforms of PDGF: aa, bb, and ab. The different isoforms bind with different specificities to the different forms of PDGFR receptor.

    There are two chains that make up PDGFR: alpha and beta. Similarly, these chains can combine to form 3 isoforms of PDGFR: alpha-alpha, beta-beta, and alpha-beta.

    The alpha-receptor can bind a and b chains, whereas the beta-receptor can bind only b chains. Thus, PDGF-AA can induce alpha-alpha dimers, PDGF-AB can induce alpha-alpha dimers and alpha-beta dimers, and PDGF BB can induce all 3 possible combinations.*The PDGF receptors are RTKs. The binding of a ligand induces dimerization. This lines up the catalytic domains of each chain. The chains can then phosphorylate one another so that they become active. The dimer can then phosphorylate and/or recruit substrates.

    Known interactions between PDGFRB and substrate molecules are shown.*List of known downstream molecules. Note that we have discussed the importance of some of these molecules in cancer pathways.*First, note the cross-talk of all the pathways. Depending on the downstream molecules in different cell types, different path ways may be more or less important. Also, a single path way can give multiple responses.

    PDGFRB actively prevents cell from dying. (anti-apoptosis)*PDGFRB plays an important role in wound healing and vascular repair. PDGFRB also plays an important role in the differentiation of erythroid and myeloid precursor cells. Expression by monocytes puts forward the idea that PDGFRB is important in monocytic differentiation.During angiogenesis, as vessels form, they recruit and are coated by mural cells that express PDGFRB. The mural cells help stabilize the new vessel. The new sprouts express PDGF-B which drives proliferation of these mural cells. Furthermore, the PDGF-B expressing cells also directs migration of these cells (b).**CMML is a from of leukemia that features monocytosis. *Found a translocation in patients with CMML. Soon after, it was found that the translocation results in a fusion protein. Since then, other unique translocations have been discovered.*4 separate gene fusions are known. The Tel/PDGFRB fusion is the most common. The ETV6 gene is another name for the Tel gene.

    Since the number of patients with variant translocations is so small, it is difficult to determine any phenotypic differences between patients with different PDGFRB fusions. **During the translocation event, the entire ligand binding site of PDGFRB is replaced by the HLH domain of the Tel protein.*Growth rates of tel/PDGFRB cells versus wild-type PDGFRB plus PDGF have not been compared. This should be done to determine if the transformation is due to constitutively active PDGFRB-dependent pathways or other mechanisms.

    *Need to be careful for acquired resistances and potential side effects.**