An antiapoptotic BCL-2 family expression index predicts the response of chronic lymphocytic leukemia to ABT-737

Author:

Al-harbi Sayer12,Hill Brian T.3,Mazumder Suparna1,Singh Kamini1,DeVecchio Jennifer1,Choudhary Gaurav14,Rybicki Lisa A.5,Kalaycio Matt3,Maciejewski Jaroslaw P.6,Houghton Janet A.1,Almasan Alexandru1

Affiliation:

1. Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH;

2. Cellular and Molecular Medicine Program, Cleveland State University, Cleveland, OH;

3. Hematologic Oncology and Blood Disorders Department, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH;

4. Department of Pathology, Case Western Reserve University, Cleveland, OH; and

5. Department of Quantitative Health Sciences, Lerner Research Institute, and

6. Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH

Abstract

Abstract The antiapoptotic BCL-2 proteins regulate lymphocyte survival and are over-expressed 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 antiapoptotic 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 < .001). In contrast, antiapoptotic 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 after 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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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