title: MiR-181 family: regulators of myeloid differentiation and acute myeloid leukemia as well as potential therapeutic targets.
abstract: MicroRNAs have been shown to play an important role in normal hematopoisis and leukemogenesis. Here, we report function and mechanisms of miR-181 family in myeloid differentiation and acute myeloid leukemia (AML). The aberrant overexpression of all the miR-181 family members (miR-181a/b/c/d) was detected in French-American-British M1, M2 and M3 subtypes of adult AML patients. By conducting gain- and loss-of-function experiments, we demonstrated that miR-181a inhibits granulocytic and macrophage-like differentiation of HL-60 cells and CD34+ hematopoietic stem/progenitor cells (HSPCs) by directly targeting and downregulating the expression of PRKCD (which then affected the PRKCD-P38-C/EBPα pathway), CTDSPL (which then affected the phosphorylation of retinoblastoma protein) and CAMKK1. The three genes were also demonstrated to be the targets of miR-181b, miR-181c and miR-181d, respectively. Significantly decreases in the expression levels of the target proteins were detected in AML patients. Inhibition of the expression of miR-181 family members owing to Lenti-miRZip-181a infection in bone marrow blasts of AML patients increased target protein expression levels and partially reversed myeloid differentiation blockage. In the mice implanted with AML CD34+ HSPCs, expression inhibition of the miR-181 family by Lenti-miRZip-181a injection improved myeloid differentiation, inhibited engraftment and infiltration of the leukemic CD34+ cells into the bone marrow and spleen, and released leukemic symptoms. In conclusion, our findings revealed new mechanism of miR-181 family in normal hematopoiesis and AML development, and suggested that expression inhibition of the miR-181 family could provide a new strategy for AML therapy.
authors.affiliation: Key State Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: R
authors.initials: R
authors.lastname: Su
authors.affiliation: Key State Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: H-S
authors.initials: HS
authors.lastname: Lin
authors.affiliation: Department of Hematology, the 303 Hospital, Nanning, Guangxi, China.
authors.forename: X-H
authors.initials: XH
authors.lastname: Zhang
authors.affiliation: Department of Hematology, the 303 Hospital, Nanning, Guangxi, China.
authors.forename: X-L
authors.initials: XL
authors.lastname: Yin
authors.affiliation: Institute of Military Hemopoietic Stem Cell, Department of Stem Cell Transplantation Center, Hospital Affiliated to Academy of Military Medical Science, Beijing, China.
authors.forename: H-M
authors.initials: HM
authors.lastname: Ning
authors.affiliation: 307-lvy Translational Medicine Center, Laboratory of Oncology, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China.
authors.forename: B
authors.initials: B
authors.lastname: Liu
authors.affiliation: Key State Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: P-F
authors.initials: PF
authors.lastname: Zhai
authors.affiliation: Key State Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: J-N
authors.initials: JN
authors.lastname: Gong
authors.affiliation: Key State Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: C
authors.initials: C
authors.lastname: Shen
authors.affiliation: Key State Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: L
authors.initials: L
authors.lastname: Song
authors.affiliation: Key State Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: J
authors.initials: J
authors.lastname: Chen
authors.affiliation: Key State Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: F
authors.initials: F
authors.lastname: Wang
authors.affiliation: Key State Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: H-L
authors.initials: HL
authors.lastname: Zhao
authors.affiliation: Key State Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Y-N
authors.initials: YN
authors.lastname: Ma
authors.affiliation: Key State Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: J
authors.initials: J
authors.lastname: Yu
authors.affiliation: Key State Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: J-W
authors.initials: JW
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001483:Base Sequence; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000235:genetics; D002417:Cattle; D002454:Cell Differentiation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006098:Granulocytes / Q000187:drug effects / Q000473:pathology; D018922:HL-60 Cells; D006412:Hematopoietic Stem Cells / Q000473:pathology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D058990:Molecular Targeted Therapy; D022423:Myeloid Cells / Q000187:drug effects / Q000473:pathology*; D051745:Protein Kinase C-delta / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014161:Transduction, Genetic; D014212:Tretinoin / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C486483:CTDSPL protein, human; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D014212:Tretinoin; C497258:PRKCD protein, human; D051745:Protein Kinase C-delta; C517695:CAMKK1 protein, human; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D013755:Tetradecanoylphorbol Acetate