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Establishment of a novel CML model using Multi-Hit technology (CMLMULTIHIT)
Start date: May 17, 2010, End date: May 16, 2012 PROJECT  FINISHED 

"The chronic phase of chronic myeloid leukaemia (CML) is characterized by the expression of the chimeric BCR-ABL gene, extended survival, and profligate growth of maturing granulocyte stemline. It provided the rationale for producing first imatinib and then a series of small molecules designed to inhibit the tyrosine kinase activity of the BCR-ABL oncoprotein, all of which can induce complete cytogenetic remissions in the majority of patients with CML in the chronic phase (CP). Selective inhibition of the BCR-ABL tyrosine kinase by imatinib is a promising new therapeutic strategy in patients with CML. Despite significant haematologic and cytogenetic responses, resistance occurs, particularly in patients with advanced disease, accelerated phase and blast crisis. The mechanism by which the transition from chronic to accelerated phase (AP) or blast crisis (BC) occurs remains poorly understood. The AP and BC phase of CML are usually manifested by additionally acquired oncogene aberrations, resistance to therapy, advancing anaplasia, progressive organomegaly, and increased blast count. Abnormal expression of some proto-oncogenes may accompany or even precede AP or BC of CML. Therefore, it is a critical issue to identify the molecule(s) which is (are) involved in the transition from CP to BC. To better understand such a complex clinical course of human CML, the generation of animal models that closely resemble the situation in people is indispensable. Our objective is to reveal the in vivo pathogenesis of CML with advanced phase using a novel mouse model. Moreover, an indispensable molecule for CML transition can be expected to be found in our study, which might be exploited for both prognostic indicators as well as new targets for therapy."
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