title: microRNA-23a, -27a and -24 synergistically regulate JAK1/Stat3 cascade and serve as novel therapeutic targets in human acute erythroid leukemia.
abstract: Acute erythroid leukemia (AEL) is characterized by lower incidence, poorer prognosis and worse survival than other types of leukemia and results from collaboration of malignant proliferation and erythroid differentiation blockage. The expression, function and therapeutic significance of noncoding RNAs in AEL have not been well studied. Here, we show that one miRNA cluster, including miR-23a, -27a and -24, is dramatically downregulated in AEL patients. Restoration of miR-23a, -27a and -24 expression induces apoptosis and erythropoiesis, inhibits adverse growth and partly relieves the leukemic symptoms of AEL patients. At the whole-genome scale, we identify that miR-23a, -27a and -24 synergistically target multiple members of the oncogenic gp130-JAK1-Stat3 pathway, and thus reinforce their inhibition on the cascade to regulate cell proliferation and apoptosis. Importantly, Ruxolitinib, a JAK1 inhibitor, could rescue the phenotypic changes induced by miR-23a, -27a and -24 inhibitors. Furthermore, miR-23a cluster-mediated-inactivation of the JAK1-Stat3 pathway promotes the expression and activity of GATA1 via inhibiting PU.1, thereby improving erythroid differentiation. Collectively, we reveal an important regulatory circuit comprising GATA1, the miR-23a cluster and gp130-JAK1-Stat3 pathway, that synergistically facilitates apoptosis and erythropoiesis and restrains adverse proliferation, indicating the therapeutic significance of miR-23a, -27a and -24 for AEL treatment.
authors.affiliation: Department of Biochemistry, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing, People's Republic of China.|Department of Cancer Biology, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: R
authors.initials: R
authors.lastname: Su
authors.affiliation: Department of Biochemistry, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing, People's Republic of China.
authors.forename: L
authors.initials: L
authors.lastname: Dong
authors.affiliation: Department of Biochemistry, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing, People's Republic of China.|Department of Gynecologic Oncology, Chongqing Cancer Institute, Chongqing, People's Republic of China.
authors.forename: D
authors.initials: D
authors.lastname: Zou
authors.affiliation: Department of Biochemistry, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing, People's Republic of China.
authors.forename: H
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Biochemistry, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing, People's Republic of China.
authors.forename: Y
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Department of Biochemistry, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing, People's Republic of China.
authors.forename: F
authors.initials: F
authors.lastname: Li
authors.affiliation: Department of Obstetrics and Gynecology, Daping Hospital, Research Institute of Surgery, Third Millitary Medical Universtiy, Chongqing, People's Republic of China.
authors.forename: P
authors.initials: P
authors.lastname: Yi
authors.affiliation: Department of Obstetrics and Gynecology, Daping Hospital, Research Institute of Surgery, Third Millitary Medical Universtiy, Chongqing, People's Republic of China.
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Biochemistry, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing, People's Republic of China.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Biochemistry, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing, People's Republic of China.
authors.forename: Y
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Pathophysiology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing, People's Republic of China.
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Biochemistry, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing, People's Republic of China.
authors.forename: F
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Biochemistry, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College (PUMC), Beijing, People's Republic of China.
authors.forename: J
authors.initials: J
authors.lastname: Yu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D004195:Disease Models, Animal; D015536:Down-Regulation; D050982:GATA1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004915:Leukemia, Erythroblastic, Acute / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D005810:Multigene Family; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D050982:GATA1 Transcription Factor; C552430:MIRN23a microRNA, human; C543845:MIRN24 microRNA, human; C531388:MIRN27 microRNA, human; D035683:MicroRNAs; D047428:Protein Kinase Inhibitors; D050796:STAT3 Transcription Factor; D053613:Janus Kinase 1