MicroRNA-486 regulates normal erythropoiesis and enhances growth and modulates drug response in CML progenitors

MicroRNAs (miRNAs) are key regulators of hematopoietic cell differentiation and may contribute to altered growth of leukemic stem cells. Using microarray-based miRNA profiling, we found that miRNA 486 (miR-486) is significantly upregulated in chronic myeloid leukemia (CML) compared with normal CD3(+) cells, particularly in the megakaryocyteerythroid progenitor population. miR-486-5p expression increased during erythroid differentiation of both CML and normal CD3(+) cells. Ectopic miR-486-5p expression enhanced in vitro erythroid differentiation of normal CD3(+) cells, whereas miR-486-5p inhibition suppressed normal CD3(+) cell growth in vitro and in vivo and inhibited erythroid differentiation and erythroid cell survival. The effects of miR-486-5p on hematopoietic cell growth and survival are mediated at least in part via regulation of Ala signaling and FOXO1 expression. Using gene expression and bionformatics analysis, together with functional screening, we identified several novel miR-486-5p target genes that may modulate erythroid differentiation. We further show that increased miR-486-5p expression in CML progenitors is related to both kinase-dependent and kinase-independent mechanisms. Inhibition of miR-486-5p reduced CML progenitor growth and enhanced apoptosis following imatinib treatment. In conclusion, our studies reveal a novel role for miR-486-5p in regulating normal hematopoiesis and of BCR-ABL induced miR-486-5p overexpression in modulating CM L progenitor growth, survival, and drug sensitivity.