BCL-2 Inhibition with ABT-199 Shows Efficacy in AML Cell Lines with Synergistic Effects upon Addition of the MEK Inhibitor GDC-0973 and Prolongs Survival in an NAS/BCL-2-Mediated Mouse Model of AML Post-MDS

Background and aims: BCL-2 activation plays a role in the progression of MDS to AML and BCL-2 inhibition may be a therapeutic target in such patients. ABT-199 is a small molecule which specifically inhibits BCL-2, approved for the treatment of CLL with TP53 mutation/17p deletion. Using the OCI-AML2 and MOLM13 AML cell lines, ABT-199 resistant cells have been derived to investigate the mechanism of drug resistance. The RAS/BCL-2 complex has been previously shown to co-localize in the mitochondria (Mito) in AML post-MDS mice and patients (Le Pogam Leuk Res 2013). To test the hypothesis that increased MCL-1 conferred ABT-199 resistance, OCI-MCL3 conditional lines in which MCL-1 could be switched on and off were studied for apoptosis and RAS/BCL-2 co-localization. In combination with our double transgenic mouse AML post-MDS preclinical model MRP8[NRASD12/BCL2] (Beurlet Blood 2013), we assessed the effect of ABT-199, and the MEK inhibitor GDC-0973.