Abstract

An emerging theme in the pathogenesis of human malignancy is the involvement of tyrosine kinases as a consequence of chromosomal translocation. However, the mechanism of transformation of this class of fusion proteins is not well understood, even for the extensively studied BCR-ABL fusion associated with t (9;22) chronic myelogenous leukemia. Our laboratory has recently cloned two new tyrosine kinase fusions, TEL- PDGFRbeta and TEL-ABL, which are associated with t (5;12) and t(9;12) chromosomal translocations respectively, in human leukemias. TEL is a new member of the ETS family of transcription factors, and contributes a highly conserved helix-loop-helix (HLH) domain to both fusions. The objective of this proposal is to determine the mechanism of transformation of TEL- PDGFRbeta and TEL-ABL by analysis of the contribution of the functional domains of TEL, PDGFRbeta and ABL. We hypothesize that transformation is due to aberrant expression and activation of the PDGFRbeta and ABL tyrosine kinases mediated by the TEL HLH domain. Preliminary studies have documented the transforming activity of the fusion proteins, and demonstrate that tyrosine kinase activity of PDGFR and ABL are absolute requirements for transforming activity. The function of the HLH domain in ETS family members is unknown. However, preliminary analysis of these fusions has led us to an interesting discovery: the TEL HLH domain appears to be a protein-protein interaction motif. This finding, in conjunction with the observation that the other TEL allele is deleted in TEL-ABL leukemia and expressed at low levels in TEL-PDGFRbeta leukemia, suggests that TEL loss of function may be important in pathogenesis of leukemia.
In Specific Aim 1, we will characterize the signal transduction properties of the TEL-PDGFRbeta fusion protein, and determine which are pivotal in mediating transformation.
In Specific Aim 2, we will analyze the signal transduction properties of TEL-ABL, and determine the common themes which unify the transforming properties of TEL-ABL and BCR-ABL.
Specific Aim 3 will focus on the role of the TEL HLH domain in transformation and the possibility that loss of function of TEL contributes to pathogenesis of leukemia. Delineation of the mechanism of transformation of TEL-PDGFRbeta TEL-ABL will be facilitated by interactions with each of the members of the Program Project, and may provide insights into therapeutic approaches to human malignancy caused by tyrosine kinase fusions.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
3P01DK050654-05S1
Application #
6499823
Study Section
Project Start
2001-09-15
Project End
2002-07-31
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
5
Fiscal Year
2001
Total Cost
$296,752
Indirect Cost

  Institution

Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02215

  Publications

Jiang, Jingrui; Griffin, James D (2010) Wnt/?-catenin Pathway Modulates the Sensitivity of the Mutant FLT3 Receptor Kinase Inhibitors in a GSK-3? Dependent Manner. Genes Cancer 1:164-76
Weisberg, E; Ray, A; Barrett, R et al. (2010) Smac mimetics: implications for enhancement of targeted therapies in leukemia. Leukemia 24:2100-9
Weisberg, Ellen; Roesel, Johannes; Furet, Pascal et al. (2010) Antileukemic Effects of Novel First- and Second-Generation FLT3 Inhibitors: Structure-Affinity Comparison. Genes Cancer 1:1021-32
Weisberg, Ellen; Choi, Hwan Geun; Ray, Arghya et al. (2010) Discovery of a small-molecule type II inhibitor of wild-type and gatekeeper mutants of BCR-ABL, PDGFRalpha, Kit, and Src kinases: novel type II inhibitor of gatekeeper mutants. Blood 115:4206-16
Weisberg, E; Deng, X; Choi, H G et al. (2010) Beneficial effects of combining a type II ATP competitive inhibitor with an allosteric competitive inhibitor of BCR-ABL for the treatment of imatinib-sensitive and imatinib-resistant CML. Leukemia 24:1375-8
Weisberg, Ellen; Choi, Hwan Geun; Barrett, Rosemary et al. (2010) Discovery and characterization of novel mutant FLT3 kinase inhibitors. Mol Cancer Ther 9:2468-77
Moldovan, George-Lucian; Madhavan, Mahesh V; Mirchandani, Kanchan D et al. (2010) DNA polymerase POLN participates in cross-link repair and homologous recombination. Mol Cell Biol 30:1088-96
Weisberg, E; Sattler, M; Ray, A et al. (2010) Drug resistance in mutant FLT3-positive AML. Oncogene 29:5120-34
Kim, Jung Min; Parmar, Kalindi; Huang, Min et al. (2009) Inactivation of murine Usp1 results in genomic instability and a Fanconi anemia phenotype. Dev Cell 16:314-20
Mercher, Thomas; Raffel, Glen D; Moore, Sandra A et al. (2009) The OTT-MAL fusion oncogene activates RBPJ-mediated transcription and induces acute megakaryoblastic leukemia in a knockin mouse model. J Clin Invest 119:852-64

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