TY - JOUR
T1 - An antiapoptotic BCL-2 family expression index predicts the response of chronic lymphocytic leukemia to ABT-737
AU - Al-harbi, Sayer
AU - Hill, Brian T.
AU - Mazumder, Suparna
AU - Singh, Kamini
AU - DeVecchio, Jennifer
AU - Choudhary, Gaurav
AU - Rybicki, Lisa A.
AU - Kalaycio, Matt
AU - Maciejewski, Jaroslaw P.
AU - Houghton, Janet A.
AU - Almasan, Alexandru
PY - 2011/9/29
Y1 - 2011/9/29
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=80053377120&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80053377120&partnerID=8YFLogxK
U2 - 10.1182/blood-2011-03-340364
DO - 10.1182/blood-2011-03-340364
M3 - Article
C2 - 21772052
AN - SCOPUS:80053377120
SN - 0006-4971
VL - 118
SP - 3579
EP - 3590
JO - Blood
JF - Blood
IS - 13
ER -