title: An antiapoptotic BCL-2 family expression index predicts the response of chronic lymphocytic leukemia to ABT-737.
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.
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Sayer
authors.initials: S
authors.lastname: Al-Harbi
authors.forename: Brian T
authors.initials: BT
authors.lastname: Hill
authors.forename: Suparna
authors.initials: S
authors.lastname: Mazumder
authors.forename: Kamini
authors.initials: K
authors.lastname: Singh
authors.forename: Jennifer
authors.initials: J
authors.lastname: Devecchio
authors.forename: Gaurav
authors.initials: G
authors.lastname: Choudhary
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Rybicki
authors.forename: Matt
authors.initials: M
authors.lastname: Kalaycio
authors.forename: Jaroslaw P
authors.initials: JP
authors.lastname: Maciejewski
authors.forename: Janet A
authors.initials: JA
authors.lastname: Houghton
authors.forename: Alexandru
authors.initials: A
authors.lastname: Almasan
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001713:Biphenyl Compounds / Q000494:pharmacology*; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D019169:Jurkat Cells; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D005810:Multigene Family / Q000187:drug effects / Q000235:genetics; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D061251:Primary Cell Culture; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
chemical_list: C501332:ABT-737; D000970:Antineoplastic Agents; D054316:Biomarkers, Pharmacological; D014408:Biomarkers, Tumor; D001713:Biphenyl Compounds; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides