Most patients with early chronic myeloid leukemia (CML) achieve durable responses to treatment with imatinib, a specific inhibitor of BCR-ABL, the tyrosine kinase responsible for CML. However, relapse is frequent in patients with advanced disease and usually is the result of point mutations in the kinase domain (KD) of BCR-ABL. Unexpectedly, KD mutant clones were also detected in imatinib-na?ve patients, consistent with a growth advantage of mutants over wild type BCR-ABL in the absence of imatinib. Moreover, mutations in the ATP-binding loop of BCR-ABL confer a poor prognosis irrespective of their sensitivity to imatinib. These observations suggest that KD mutations may alter the biology of the CML in addition to and independent of their role in conferring imatinib resistance. Consistent with this, we have preliminary data that show differences in transformation potency between some mutants and wild type BCR-ABL. While these differences may be related to altered kinase activity in some cases, we have data showing that KD mutations also alter signal transduction. We propose to comprehensively analyze a panel of BCR-ABL mutants isolated from CML patients. We will determine kinetic parameters of kinase activity, activation of signaling pathways (using a novel extremely sensitive phosphoproteomics approach) and gene expression profiles, and correlate these data with transformation potency in biological assays. We will integrate this information to identify candidate mediators of a more or less aggressive phenotype that will then be validated in the appropriate biological systems. This study has two global objectives. Firstly, we will clarify role of KD mutations for disease progression of CML. Given that the mechanisms responsible for progression of CML form the chronic phase to accelerated and blastic phase are poorly understood, this will increase the knowledge of CML biology. Secondly, we will identify mediators that significantly affect transformation potency in a tightly controlled experimental system. Using this approach, we aim to identify novel therapeutic targets that could be exploited for the treatment of CML, and further, for other types of cancer for which there are currently no effective therapies available. Some patients with chronic myeloid leukemia relapse on therapy with imatinib (Gleevec), because they develop mutations in a critical protein. There is evidence that some of these mutations may also contribute to leukemia progression and confer a very bad prognosis to patients. We will study precisely how the mutations make the leukemia more aggressive, with the aim of identifying proteins that are critical in mediating the more aggressive behavior. Such crucial proteins may then be exploited as drug targets for the treatment of chronic myeloid leukemia, and further, for other types of cancer.
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