Chronic Myelogenous Leukemia (CML) is caused by BCR/ABL, a constitutive tyrosine kinase oncoprotein. Standard chemotherapy can control leukocytosis during the initial chronic phase of CML, but does nothing to alter the inevitable development of blast crisis, an acute leukemia that ultimately proves fatal. Alpha-interferon (a-IFN) induces hematologic and cytogenetic remission, postpones blast crisis, and prolongs survival in CML patients. cx-IFN restores critical adhesion defects and stimulates active immune suppression of CML progenitors, but our knowledge of interferon mechanisms is incomplete. In preliminary studies we have uncovered roles for two interferon inducible proteins that suggest novel hypotheses to explain the therapeutic effect of interferons in CML. The Interferon Consensus Sequence Binding Protein (ICSBP), implicated in CML causation by gene knock-out in mice, inhibits BCRIABL-mediated proliferation of hematopoietic cells and sensitizes leukemia cell lines to immune rejection. We will characterize the mechanism of ICSBP-induced immunity against BCR/ABL-induced leukemia. The Interferon Inducible Protein 9-27/Leu13, an adhesion molecule that inhibits cell proliferation, was found in an array-based expression screen to be down-regulated by BCRJABL and up-regulated by ICSBP. We will investigate the lIP 9-27/Leul3 protein as a potentially critical point of convergence of BCRIABL and interferon signaling. Our expression screen also identified a number of novel targets of BCR/ABL action, including cyclin D2. We have demonstrated that cyclin D2-deficient mice have a profound cell-intrinsic resistance to BCRJABL transformation, and we will study how cyclins D1, D2, and D3 influence the capacity of BCR/ABL to induce myeloid and lymphoid leukemia in mice. This proposal seeks to advance our fundamental knowledge of CML biology and therapeutic mechanisms in hopes of refining future treatment strategies.

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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Mufson, R Allan
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Whitehead Institute for Biomedical Research
United States
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