The broad objective is to elucidate the molecular mechanism by which the bcr-abl oncogene acts in the pathogenesis of chronic myelogenous leukemia (CML). The bcr-abl oncogene is created by a chromosomal translocation, which fuses a portion of the breakpoint cluster region (bcr) gene and most of the abl gene. The project focuses on the interaction of Bcr-Abl with other proteins. The Abl tyrosine kinase activity in Bcr-Abl is required for the neoplastic transformation, indicating that Abl induces leukemia through phosphorylation of target proteins. Dr. Ren's preliminary data indicate that Abl recruits specific substrates via protein-protein interactions mediated by its non-catalytic domains. Dr. Ren has shown that coexpression of Bcr-Abl and the Abl-binding protein (ABP) Grb2 induces a CML-like disease in mice. Therefore, he hypothesizes that the ABPs play important roles in regulating and mediating the oncogenic functions of Abl. In this project, he will further identify ABPs from the leukemic cells, and investigate the effect of the protein-protein interactions on the oncogenic function of Bcr-Abl. The long-term objectives are to determine whether the oncogenic function of Bcr-Abl is regulated and/or mediated by its binding proteins, and if so, whether the malignant potential of Bcr-Abl can be mitigated by controlling these interactions. Such information will help to elucidate the leukemogenic pathway activated by Bcr-Abl and help to develop therapeutic drugs for human leukemia. Accordingly, the specific aims of the project are as follows: (1) To test the hypothesis that the association of Grb2 or other ABPs with Bcr-Abl is required for the transformation of Bcr-Abl via examining the effect of the mutations in Bcr-Abl that interrupt ABP- binding on neoplastic transformation; (2) To test the hypothesis that cells of hematopoietic lineage derived from CML patients contain a unique set of ABPs by identifying the potential targets of Bcr-Abl from CML cells; (3) To test the hypothesis that the malignant potential of Bcr-Abl can be mitigated by interrupting the interaction between Bcr-Abl and ABPs in trans by examining the ability of overexpression of ABPs or their mutant polypeptides to block cellular transformation.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Pathology B Study Section (PTHB)
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Brandeis University
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Baum, Karina J; Ren, Ruibao (2008) Effect of Ras inhibition in hematopoiesis and BCR/ABL leukemogenesis. J Hematol Oncol 1:5
Acquaviva, Jaime; Chen, Xiaoren; Ren, Ruibao (2008) IRF-4 functions as a tumor suppressor in early B-cell development. Blood 112:3798-806
Parikh, Chaitali; Ren, Ruibao (2008) Mouse model for NRAS-induced leukemogenesis. Methods Enzymol 439:15-24
Parikh, Chaitali; Subrahmanyam, Ramesh; Ren, Ruibao (2006) Oncogenic NRAS rapidly and efficiently induces CMML- and AML-like diseases in mice. Blood 108:2349-57
Ren, Ruibao (2004) Modeling the dosage effect of oncogenes in leukemogenesis. Curr Opin Hematol 11:25-34
Cuenco, Grace M; Ren, Ruibao (2004) Both AML1 and EVI1 oncogenic components are required for the cooperation of AML1/MDS1/EVI1 with BCR/ABL in the induction of acute myelogenous leukemia in mice. Oncogene 23:569-79
Wertheim, Jason A; Perera, Samanthi A; Hammer, Daniel A et al. (2003) Localization of BCR-ABL to F-actin regulates cell adhesion but does not attenuate CML development. Blood 102:2220-8
Ren, Ruibao (2002) Dissecting the molecular mechanism of chronic myelogenous leukemia using murine models. Leuk Lymphoma 43:1549-61
Ren, Ruibao (2002) The molecular mechanism of chronic myelogenous leukemia and its therapeutic implications: studies in a murine model. Oncogene 21:8629-42
Zhang, X; Subrahmanyam, R; Wong, R et al. (2001) The NH(2)-terminal coiled-coil domain and tyrosine 177 play important roles in induction of a myeloproliferative disease in mice by Bcr-Abl. Mol Cell Biol 21:840-53

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