Bcl-2 protein family expression pattern determines synergistic pro-apoptotic effects of BH3 mimetics with hemisynthetic cardiac glycoside UNBS1450 in acute myeloid leukemia

Resistance to apoptotic cell death 1 owing to overexpression of anti-apoptotic Bcl-2 family proteins including Bcl-2, Bcl-xL or Mcl-1 is considered an interesting druggable target for the treatment of hematological malignancies including acute myeloid leukemia. In fact, BH3 mimetics 2 like ABT-199 (venetoclax) 3 reverse the inhibitory function of anti-apoptotic Bcl-2 proteins. 4 Dependency on Bcl-2 family protein expression requests BH3 profiling to efficiently stratify patients potentially benefiting from ABT-199 therapy. 5 Most often, Mcl-1 is considered a main resistance factor 2 and recently a first class of selective Mcl-1 inhibitors was characterized. 6 As an alternative to functional inhibitors, we previously described proteasome-dependent downregulation of Mcl-1 expression 7 , 8 by cardiac glycoside UNBS1450. 8 , 9 , 10 We hypothesize here that a combination of UNBS1450 with a BH3 mimetic would affect acute myeloid leukemia (AML) subtypes especially ‘addicted’ to Mcl-1. To provide a targeted therapeutic approach, we describe the synergistic antileukemic effect of ABT-199 with UNBS1450 in cell lines, colony formation assays, zebrafish xenografts and validate results in primary cells from 23 de novo AML patients.