MicroRNA-146a and AMD3100, two ways to control CXCR4 expression in acute myeloid leukemias

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.

NRF2-driven miR-125B1 and miR-29B1 transcriptional regulation controls a novel anti-apoptotic miRNA regulatory network for AML survival

“…37 Moreover, we also noted that high NRF2 activity caused a decrease in the expression of miRNAs, which includes miR-154, miR146a and miR-181B. All these miRNAs have been shown to be of interest in AML with miR-146a being shown to have low expression in AML, which correlates with high expression of its target gene CXCR4, 38 which in a separate study has been shown to be regulated by NRF2 in human HSC. 39 Consequently in human AML, NRF2 not only regulates key genes involved in the reaction to oxidative stress but also regulates miRNAs that appear to have a broader impact on gene expression and regulation.…”

Differential hypoxic regulation of the microRNA-146a/CXCR4 pathway in normal and leukemic monocytic cells: impact on response to chemotherapy

“…Thus, the decrease of CXCR4 protein levels observed under severe hypoxia ( Figure 1F) is associated with a marked increase of miR-146a ( Figure 1D) which blocks CXCR4 mRNA translation, according to the previously described mechanism of post-transcriptional control of CXCR4 expression by miR-146a targeting. 39 Altogether, these data show that severe hypoxia impairs monocytic differentiation of hematopoietic progenitor cells and activates miR-146a/CXCR4 regulation to control CXCR4 level. …”

“…39 We also reported that in acute monocytic leukemia (AML-M5), a high CXCR4 protein level is associated with low/absent miR-146a expression. 39 We then showed that enforced miR-146a expression in leukemic cells decreases the level of CXCR4 protein and improves the sensitivity of these cells to drugs. …”

“…RNA and protein samples were prepared as described elsewhere. 39 Leukemic cell lines, U937 and HL-60, were grown in RPMI medium supplemented with 10% fetal calf serum (Gibco, Carlsbad, CA, USA). …”

MicroRNAs; easy and potent targets in optimizing therapeutic methods in reparative angiogenesis

“…CXCR4 is a direct target of miR‐150, ‐146a, ‐133 and ‐1 in PCs 57, 61, 64, whereas miR‐23 (miR‐23, ‐24, ‐27) and 221 (miR‐221, ‐222, ‐223) targets SDF‐1α 63, 65, 66. Thereby, up‐regulation of these miRNAs versus miR‐126 in ischaemia respectively represses PC requirement, directional migration and retention of PCs within injured sites 65, 66.…”