An anti-apoptotic Bcl-2 family expression index predicts the response o fCLL to ABT-737

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BlankAn anti-apoptotic Bcl-2 family expression index predicts the response of

chronic lymphocytic leukemia to ABT-737.

S Al-Harbi, BT Hill, S Mazumder, K Singh, J Devecchio, G Choudhary, LA Rybicki,

M Kalaycio, JP Maciejewski, JA Houghton, and A Almasan

Blood, July 19, 2011; .

Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic,

Cleveland, OH, United States;

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.

PMID: 21772052