Life and Death of Leukemic Cells Under Bcr-Abl Signaling Control

The constitutive tyrosine kinase (TK) activity of the Bcr-Abl fusion oncoprotein, the product of the Philadelphia (Ph1)-chromosome, is essential for factor-independent cell proliferation and survival in Bcr-Abl-positive (Bcr-Abl+) leukemias, such as chronic myelogenous leukemia (CML) or Ph1-positve acute leukemias. Currently, Bcr-Abl TK inhibitors (TKIs) such as imatinib mesylate are regarded as the most promising therapeutic strategy for Bcr-Abl+ leukemias, but recent evidence suggests that Bcr-Abl TKIs are unlikely to lead ultimately to complete elimination of leukemic cells. To develop more effective therapeutic strategies for complete leukemia cell elimination, it is essential to understand how cellular life and death decisions are regulated in Bcr-Abl+ leukemias. This paper reviews recent knowledge related to the biologic and molecular regulatory mechanisms for cellular survival and death under Bcr-Abl signaling control in leukemic cells, and focuses on Bcl-2 family-regulated apoptosis, especially on the role of BH3-only proteins, such as Bim, as well as on non-apoptotic programmed cell death, and autophagy. Implications for future therapeutic strategies for Bcr-Abl+ leukemia are also discussed.