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

ABSTRACT: 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 BH₃-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, A121047

SUBMITTER: O' Reilly E 

PROVIDER: S-EPMC6202320 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature