title: MicroRNA-29a and microRNA-142-3p are regulators of myeloid differentiation and acute myeloid leukemia.
abstract: Although microRNAs (miRNAs) are increasingly linked to various physiologic processes, including hematopoiesis, their function in the myeloid development is poorly understood. We detected up-regulation of miR-29a and miR-142-3p during myeloid differentiation in leukemia cell lines and CD34(+) hematopoietic stem/progenitor cells. By gain-of-function and loss-of-function experiments, we demonstrated that both miRNAs promote the phorbol 12-myristate 13-acetate-induced monocytic and all-trans-retinoic acid-induced granulocytic differentiation of HL-60, THP-1, or NB4 cells. Both the miRNAs directly inhibited cyclin T2 gene, preventing the release of hypophosphorylated retinoblastoma and resulting in induction of monocytic differentiation. In addition, a target of miR-29a, cyclin-dependent kinase 6 gene, and a target of miR-142-3p, TGF-β-activated kinase 1/MAP3K7 binding protein 2 gene, are involved in the regulation of both monocytic and granulocytic differentiation. A significant decrease of miR-29a and 142-3p levels and an obvious increase in their target protein levels were also observed in blasts from acute myeloid leukemia. By lentivirus-mediated gene transfer, we demonstrated that enforced expression of either miR-29a or miR-142-3p in hematopoietic stem/progenitor cells from healthy controls and acute myeloid leukemia patients down-regulated expression of their targets and promoted myeloid differentiation. These findings confirm that miR-29a and miR-142-3p are key regulators of normal myeloid differentiation and their reduced expression is involved in acute myeloid leukemia development.
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Xiao-Shuang
authors.initials: XS
authors.lastname: Wang
authors.forename: Jia-Nan
authors.initials: JN
authors.lastname: Gong
authors.forename: Jia
authors.initials: J
authors.lastname: Yu
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.forename: Xin-Hua
authors.initials: XH
authors.lastname: Zhang
authors.forename: Xiao-Lin
authors.initials: XL
authors.lastname: Yin
authors.forename: Zhen-Qing
authors.initials: ZQ
authors.lastname: Tan
authors.forename: Zi-Mian
authors.initials: ZM
authors.lastname: Luo
authors.forename: Gui-Hua
authors.initials: GH
authors.lastname: Yang
authors.forename: Chao
authors.initials: C
authors.lastname: Shen
authors.forename: Jun-Wu
authors.initials: JW
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D002273:Carcinogens / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects / Q000502:physiology; D057809:HEK293 Cells; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D022423:Myeloid Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D002273:Carcinogens; C555159:MIRN142 microRNA, human; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D014212:Tretinoin; D013755:Tetradecanoylphorbol Acetate