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-XL as previously thought. Instead, BMSCs induced Mcl-1 expression over Bcl-2 and/or Bcl-XL 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 BH3-mimetics. Furthermore, combined inhibition of Bcl-2/Bcl-XL 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-XL 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.
Highlights
Acute myeloid leukemia (AML) is a complex disease driven by a combination of genetic and epigenetic alterations in the hematopoietic stem or progenitor cells
We show that bone marrow stromal cells (BMSCs) provide resistance against BH3-mimetics, cytarabine (AraC) and daunorubicin (DnR) and that this protection is pronounced in the CD34+/CD38− cell population
HS-5 cells were chosen over primary BMSCs of Acute myeloid leukaemia (AML) patients, as the latter were found to be prone to senescence under ex vivo culture[20]
Summary
Acute myeloid leukemia (AML) is a complex disease driven by a combination of genetic and epigenetic alterations in the hematopoietic stem or progenitor cells. We determined the role of anti-apoptotic Bcl-2 proteins as effectors of bone marrow stroma-mediated drug resistance in AML blasts and the CD34+/CD38− cells representing a population enriched for leukemic stem cells (LSC)[19].
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