IDENTIFICATION OF POTENT BH3-MIMETIC COMBINATIONS TARGETING PRO-SURVIVAL PATHWAYS IN HUMAN B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA

Precursor-B acute lymphoblastic leukemia (B-ALL) is an aggressive hematological malignancy. Relapsed disease has a poor prognosis despite improved outcomes with tyrosine kinase inhibitors (TKIs) and immunotherapeutic approaches such as CAR-T cells. Targeting cell survival with small molecule BH3 mimetic inhibitors of BCL-2, BCL-XL or MCL1 is an emerging therapeutic option. We report that dual BH3 mimetic targeting of BCL-2/MCL1 is strongly synergistic in SUPB15, BV173, MUTZ5 and MHHCALL4 B-ALL cell lines and was more effective than single BH3 mimetic combinations with dexamethasone (DXM) or TKIs (dasatinib/ruxolitinib). In patient samples, combined BCL-2/MCL1 targeting lowered the LC50 by 10-1000 fold (LC50