Abstract

The overall goal of this Program Project is to study the basic biology of signal hematopoietic cells as it relates to human disease status. Abnormalities in signal transduction can lead to diseases of hematopoietic cell overproduction (leukemia) or underproduction (cytopenias). There are two major signal transduction pathways defined in hematopoietic cells: the RAS/Raf/MAP kinase pathways and the JAK/STAT pathway that underlie hematopoietic disease. Project 2 will focus on the interaction between BCR/ABL and the CRKL adapter protein and its functional importance in the pathogenesis of stable phase CML. Project 3 will investigate the function of the phosphatase, SHPTP1, and its ability to associate with and down- modulate the CSF-1 Receptor and BCR/ABL signals. Project 4 will investigate the signal transduction mechanism of two newly-identified hematopoietic oncoproteins, Te1/PDGFR and Tel/ABL. An Administrative Core and an Animal Core 9001 are also outlined. Multiple interactions among the four projects are also delineated.

  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 #
3P01DK050654-03S1
Application #
2879010
Study Section
Special Emphasis Panel (SRC (01))
Program Officer
Badman, David G
Project Start
1998-09-25
Project End
1999-07-31
Budget Start
1998-09-25
Budget End
1999-07-31
Support Year
3
Fiscal Year
1998
Total Cost
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
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
Wojiski, S; Guibal, F C; Kindler, T et al. (2009) PML-RARalpha initiates leukemia by conferring properties of self-renewal to committed promyelocytic progenitors. Leukemia 23:1462-71

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