Abstract
Complex molecular cross talk between stromal cells and the leukemic cells in bone marrow is known to contribute significantly towards drug-resistance. Here, we have identified the molecular events that lead to stromal cells mediated therapy-resistance in acute myeloid leukemia (AML). Our work demonstrates that stromal cells downregulate miR-23a-5p levels in leukemic cells to protect them from the chemotherapy induced apoptosis. Downregulation of miR-23a-5p in leukemic cells leads to upregulation of protective autophagy by targeting TLR2 expression. Further, autophagy inhibitors when used as adjuvants along with conventional drugs can improve drug sensitivity in vitro as well in vivo in a mouse model of leukemia. Our work also demonstrates that this mechanism of bone marrow stromal cell mediated regulation of miR-23a-5p levels and subsequent molecular events are relevant predominantly in myeloid leukemia. Our results illustrate the critical and dynamic role of the bone marrow microenvironment in modulating miRNA expression in leukemic cells which could contribute significantly to drug resistance and subsequent relapse, possibly through persistence of minimal residual disease in this environment.
Highlights
Bone-marrow microenvironment is known to be actively involved in an onco-protective role for metastatic cancer cells, as well as in leukemia[1,2]
Since miRNAs are known to be one of the major regulators of therapy-resistance in different cancers, we focused on deciphering if cellular miRNAs are differentially expressed in leukemic cells upon stromal co-culture to mediate this protective effect
Accumulating evidence suggests that bone marrow stromal micro-environment act as sanctuary site for leukemic cells and affords protection from conventional chemotherapy agents
Summary
Bone-marrow microenvironment is known to be actively involved in an onco-protective role for metastatic cancer cells, as well as in leukemia[1,2]. The molecular mechanism and molecular players involved in contributing towards minimal residual disease and drug resistance are highly dynamic. This can be achieved by stromaderived secretory factors such as cytokines and chemokines, which help in homing, survival, and growth of the cancer cell in bone-marrow, as well as provide protection. Amongst the different AML subtypes, APL (AML-M3) is known to have best response to therapy when arsenic trioxide (ATO) based regimens are used.
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