Repression of Mcl-1 expression by the CDC7/CDK9 inhibitor PHA-767491 overcomes bone marrow stroma-mediated drug resistance in AML

Acute myeloid leukaemia (AML) is an aggressive cancer with 50–75% of patients relapsing even after successful chemotherapy. The role of the bone marrow microenvironment (BMM) in protecting AML cells from chemotherapeutics and causing consequent relapse is increasingly recognised. However the role that the anti-apoptotic Bcl-2 proteins play as effectors of BMM-mediated drug resistance are less understood. Here we show that bone marrow mesenchymal stromal cells (BMSC) provide resistance to AML cells against BH(3)-mimetics, cytarabine and daunorubicin, but this is not mediated by Bcl-2 and/or Bcl-X(L) as previously thought. Instead, BMSCs induced Mcl-1 expression over Bcl-2 and/or Bcl-X(L) in AML cells and inhibition of Mcl-1 with a small-molecule inhibitor, A1210477, or repressing its expression with the CDC7/CDK9 dual-inhibitor, PHA-767491 restored sensitivity to BH(3)-mimetics. Furthermore, combined inhibition of Bcl-2/Bcl-X(L) and Mcl-1 could revert BMSC-mediated resistance against cytarabine + daunorubicin. Importantly, the CD34(+)/CD38(−) leukemic stem cell-encompassing population was equally sensitive to the combination of PHA-767491 and ABT-737. These results indicate that Bcl-2/Bcl-X(L) and Mcl-1 act in a redundant fashion as effectors of BMM-mediated AML drug resistance and highlight the potential of Mcl-1-repression to revert BMM-mediated drug resistance in the leukemic stem cell population, thus, prevent disease relapse and ultimately improve patient survival.