Anti-Apoptotic Mechanisms in BCR/ABL Leukemogenesis

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The ability of BCR/ABL oncoproteins to induce leukemic transformation of hematopoietic cells depends on their tyrosine kinase activity, which is essential for the recruitment and the activation of multiple pathways (i.e., MAPkinase, Jun Kinase, PI-3k) that transduce oncogenic signals. Some of these pathways are also required for the anti-apoptotic effect of BCR/ABL. The objective of this proposal is t to delineate mechanisms involved in the survival-promoting effect of BCR/ABL and to assess the contribution of anti-apoptotic pathways for the leukmogenic potential of BCR/ABL. To this purpose, we will investigate mechanisms whereby three anti-apoptotic pathways regulated by BCR/ABL (Akt and STAT5 activation, mitochondrial targeting of Raf-1) promote cell survival and contribute to leukemogenesis. These studies should lead to a better understanding of the role of anti-apoptotic mechanisms in BCR/ABL leukemogenesis and the potential development of anti-leukemia therapies interfering with BCR/ABL-regulated survival signals.