Anti-Apoptotic Mechanisms in BCR/ABL Leukemogenesis

BCR/ABL癌蛋白诱导造血细胞白血病转化的能力取决于它们的酪氨酸激酶活性，酪氨酸激酶活性对于募集和激活多种通路（即map激酶、Jun激酶、PI-3k）至关重要，这些通路可转导致癌信号。其中一些通路也是BCR/ABL抗凋亡作用所必需的。本研究的目的是描述BCR/ABL促进生存的机制，并评估抗凋亡途径对BCR/ABL致白血病潜能的贡献。为此，我们将研究BCR/ABL调节的三种抗凋亡途径（Akt和STAT5激活，线粒体靶向Raf-1）促进细胞存活和促进白血病发生的机制。这些研究将有助于更好地理解抗凋亡机制在BCR/ABL白血病发生中的作用，以及干扰BCR/ABL调节的生存信号的抗白血病治疗的潜在发展。

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.