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Targeting the Bcl-2 family in B-cell chronic lymphocytic leukemia


B-cell chronic lymphocytic leukemia (CLL) is the most common leukemia in human adults of the western world and no definitive cure is yet available. One key factor in CLL pathogenesis and disease progression is misbalanced Bcl-2 cell death machinery that is shifted towards protection from apoptosis. Thus, strategies to counteract the antiapoptotic action of the Bcl-2 family in CLL cells are being explored. The Bcl-2 family is composed of a growing number of proteins related to Bcl-2 by sequence homology and their interactions regulate the cell’s decision to die. The features of one particular subclass, the BH3-only proteins, are being studied and exploited for the development of therapeutic anticancer approaches that specifically target antiapoptotic Bcl-2 proteins overexpressed in tumors, including CLL. Preclinical and clinical efficacy and toxicity of the most effective among these ‘BH3 mimetics’ are presented, together with a model that accounts for the differential sensitivity of CLL and normal cells to Bcl-2 neutralization.

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