title: MicroRNA-486 regulates normal erythropoiesis and enhances growth and modulates drug response in CML progenitors.
abstract: 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 CD34(+) cells, particularly in the megakaryocyte-erythroid progenitor population. miR-486-5p expression increased during erythroid differentiation of both CML and normal CD34(+) cells. Ectopic miR-486-5p expression enhanced in vitro erythroid differentiation of normal CD34(+) cells, whereas miR-486-5p inhibition suppressed normal CD34(+) 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 AKT signaling and FOXO1 expression. Using gene expression and bioinformatics 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 CML progenitor growth, survival, and drug sensitivity.
authors.affiliation: Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, CA; Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, People's Republic of China; and.
authors.forename: Li-Sheng
authors.initials: LS
authors.lastname: Wang
authors.affiliation: Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, CA;
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, CA;
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.affiliation: Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, CA;
authors.forename: Su
authors.initials: S
authors.lastname: Chu
authors.affiliation: Department of Information Sciences and.
authors.forename: Keh-Dong
authors.initials: KD
authors.lastname: Shiang
authors.affiliation: Department of Information Sciences and.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, People's Republic of China; and.
authors.forename: Hui-Yan
authors.initials: HY
authors.lastname: Sun
authors.affiliation: Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, People's Republic of China; and.
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Experimental Hematology, Beijing Institute of Radiation Medicine, Beijing, People's Republic of China; and.
authors.forename: Feng-Jun
authors.initials: FJ
authors.lastname: Xiao
authors.affiliation: Department of Molecular and Cellular Biology, City of Hope National Medical Center, Duarte, CA.
authors.forename: Guihua
authors.initials: G
authors.lastname: Sun
authors.affiliation: Department of Molecular and Cellular Biology, City of Hope National Medical Center, Duarte, CA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Rossi
authors.affiliation: Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, CA;
authors.forename: YinWei
authors.initials: Y
authors.lastname: Ho
authors.affiliation: Division of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, Duarte, CA;
authors.forename: Ravi
authors.initials: R
authors.lastname: Bhatia
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004920:Erythropoiesis / Q000235:genetics*; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics* / Q000473:pathology; D055015:Megakaryocyte-Erythroid Progenitor Cells / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000502:physiology*
chemical_list: C560945:MIRN486 microRNA, human; D035683:MicroRNAs