Blood Journal
Leading the way in experimental and clinical research in hematology

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

  1. Sayer Al-harbi1,
  2. Brian T. Hill2,
  3. Suparna Mazumder1,
  4. Kamini Singh1,
  5. Jennifer DeVecchio1,
  6. Gaurav Choudhary3,
  7. Lisa A. Rybicki4,
  8. Matt Kalaycio2,
  9. Jaroslaw P. Maciejewski5,
  10. Janet A. Houghton1, and
  11. Alexandru Almasan1,*
  1. 1 Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States;
  2. 2 Hematologic Oncology and Blood Disorders Department, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, United States;
  3. 3 Department of Pathology, Case Western Reserve University, Cleveland, OH, United States;
  4. 4 Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, United States;
  5. 5 Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, United States
  1. * Corresponding author; email: almasaa{at}


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.