An antiapoptotic 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, Alexandru Almasan

Research output: Contribution to journalArticlepeer-review

70 Scopus citations

Abstract

The antiapoptotic 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 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.

Original languageEnglish (US)
Pages (from-to)3579-3590
Number of pages12
JournalBlood
Volume118
Issue number13
DOIs
StatePublished - Sep 29 2011
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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