Abstract
CXCR4 is a negative prognostic marker in acute myeloid leukemias (AMLs). Therefore, it is necessary to develop novel ways to inhibit CXCR4 expression in leukemia. AMD3100 is an inhibitor of CXCR4 currently used to mobilize cancer cells. CXCR4 is a target of microRNA (miR)-146a that may represent a new tool to inhibit CXCR4 expression. We then investigated CXCR4 regulation by miR-146a in primary AMLs and found an inverse correlation between miR-146a and CXCR4 protein expression levels in all AML subtypes. As the lowest miR-146a expression levels were observed in M5 AML, we analyzed the control of CXCR4 expression by miR-146a in normal and leukemic monocytic cells and showed that the regulatory miR-146a/CXCR4 pathway operates during monocytopoiesis, but is deregulated in AMLs. AMD3100 treatment and miR-146a overexpression were used to inhibit CXCR4 in leukemic cells. AMD3100 treatment induces the decrease of CXCR4 protein expression, associated with miR-146a increase, and increases sensitivity of leukemic blast cells to cytotoxic drugs, this effect being further enhanced by miR-146a overexpression. Altogether our data indicate that miR-146a and AMD3100, acting through different mechanism, downmodulate CXCR4 protein levels, impair leukemic cell proliferation and then may be used in combination with anti-leukemia drugs, for development of new therapeutic strategies.
Highlights
Several mechanisms regulate the interaction of normal and leukemic bone marrow (BM) stem/progenitor cells with the BM microenvironment, consisting of extracellular matrix and the stromal cells
We provide evidence that in M1 to M5 acute myeloid leukemia (AML), CXCR4 expression is regulated by miR-146a through a mechanism similar to that observed in leukemic cell lines and in normal megakaryocytes.[17]
We investigated miR-146a and CXCR4 expression among 38 AMLs mainly pertaining to five subgroups from M1 to M5 FAB subsets (7 M1; 7 M2; 6 M3; 11 M4; 7 M5), as compared with normal CD34 þ HPCs
Summary
Several mechanisms regulate the interaction of normal and leukemic bone marrow (BM) stem/progenitor cells with the BM microenvironment, consisting of extracellular matrix and the stromal cells. This interaction has a key role in the control of survival, proliferation, self-renewal, chemoresistance and mobilization of stem/progenitor cells. We investigated and confirmed the role of miR146a in regulating CXCR4 protein expression at protein level, in normal and leukemic monocytic cells. AMD3100 treatment of leukemic cells impair cell proliferation, whereas the CXCR4 protein level is downmodulated and miR-146a expression increases. AMD3100 treatment increases leukemic blast cell sensitivity to anticancer drug treatment by downmodulating membrane CXCR4 protein levels, this phenomenon being potentiated by miR-146a overexpression. These observations shed light on the molecular mechanisms regulating CXCR4 expression by miR-146a in normal and leukemic cells
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