An anti-apoptotic Bcl-2 family expression index predicts the response of chronic lymphocytic leukemia to ABT-737

Sayer Al-harbi, Brian T. Hill, Suparna Mazumder, Kamini Singh, Jennifer DeVecchio, Gaurav Choudhary, Lisa A. Rybicki, Matt Kalaycio, Jaroslaw P. Maciejewski, Janet A. Houghton and Alexandru Almasan


The anti-apoptotic Bcl-2 proteins regulate lymphocyte survival and are overexpressed in lymphoid malignancies, including chronic lymphocytic leukemia. The small molecule inhibitor ABT-737 binds with high affinity to Bcl-2, Bcl-xl, and Bcl-w but with low affinity to Mcl-1, Bfl-1, and Bcl-b. The active analog of ABT-737, navitoclax has shown a high therapeutic index in lymphoid malignancies; developing a predictive marker for it would be clinically valuable for patient selection or choice of drug combinations. Here we used RT-PCR as a highly sensitive and quantitative assay to compare expression of anti-apoptotic Bcl-2 genes that are known to be targeted by ABT-737. Our findings reveal that the relative ratio of Mcl-1 and Bfl-1 to Bcl-2 expression provides a highly significant linear correlation with ABT-737 sensitivity (r=0.6, P<0.001). In contrast, anti-apoptotic transcript levels, used individually or in combination for high or low affinity ABT-737-binding proteins could not predict ABT-737 sensitivity. The (Mcl-1 + Bfl-1)/Bcl-2 ratio was validated in a panel of leukemic cell lines subjected to genetic and pharmacologic manipulations. Changes following ABT-737 treatment included increased expression of Bfl-1 and Bcl-b that may contribute to treatment resistance. This study defines a highly significant Bcl-2 expression index for predicting the response of CLL to ABT-737.

  • Submitted March 2, 2011.
  • Accepted July 1, 2011.