title: MicroRNA-9 promotes proliferation of leukemia cells in adult CD34-positive acute myeloid leukemia with normal karyotype by downregulation of Hes1.
abstract: Acute myeloid leukemia (AML) is a group of heterogeneous hematopoietic malignancies sustained by leukemic stem cells (LSCs) that can resist treatment. Previously, we found that low expression of Hes1 was a poor prognostic factor for AML. However, the activation status of Hes1 and its regulation in LSCs and leukemic progenitors (LPs) as well as normal hematopoietic stem cells (HSCs) in Hes1-low AML patients have not been elucidated. In this study, the expression of Hes1 in LSCs and LPs was analyzed in adult CD34(+) Hes1-low AML with normal karyotype and the upstream microRNA (miRNA) regulators were screened. Our results showed that the level of either Hes1 or p21 was lower in LSCs or LPs than in HSCs whereas the level of miR-9 was highest in LPs and lowest in HSCs. An inverse correlation was observed in the expression of Hes1 and miR-9. Furthermore, we validated miR-9 as one of the regulators of Hes1 by reporter gene analysis. Knockdown of miR-9 by lentivirus infection suppressed the proliferation of AML cells by the induction of G0 arrest and apoptosis in vitro. Moreover, knockdown of miR-9 resulted in decreased circulating leukemic cell counts in peripheral blood and bone marrow, attenuated splenomegaly, and prolonged survival in a xenotransplant mouse model. Our results indicate that the miR-9 plays an important role in supporting AML cell growth and survival by downregulation of Hes1 and that miR-9 has potential as a therapeutic target for treating AML.
authors.affiliation: Department of Hematology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China.
authors.forename: Chen
authors.initials: C
authors.lastname: Tian
authors.affiliation: Department of Hematopathology, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
authors.forename: M James
authors.initials: MJ
authors.lastname: You
authors.affiliation: Department of Hematology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Department of Hematology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhu
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300020, People's Republic of China. zhenggg@ihcams.ac.cn.
authors.forename: Guoguang
authors.initials: G
authors.lastname: Zheng
authors.affiliation: Department of Hematology, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, 300060, People's Republic of China. yizhuozhang111@163.com.
authors.forename: Yizhuo
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism*; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002453:Cell Cycle; D049109:Cell Proliferation; D015536:Down-Regulation; D005260:Female; D005500:Follow-Up Studies; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology; D006801:Humans; D059785:Karyotype; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009367:Neoplasm Staging; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000072056:Transcription Factor HES-1 / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D055815:Young Adult
chemical_list: D018952:Antigens, CD34; D014408:Biomarkers, Tumor; C541874:MIRN92 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D000072056:Transcription Factor HES-1; C078493:HES1 protein, human
keywords: Acute myeloid leukemia; Hematopoietic stem cells; Hes1; Leukemic progenitors; Leukemic stem cells; MicroRNA-9