title: miR-638 regulates differentiation and proliferation in leukemic cells by targeting cyclin-dependent kinase 2.
abstract: MicroRNAs have been extensively studied as regulators of hematopoiesis and leukemogenesis. We identified miR-638 as a novel regulator in myeloid differentiation and proliferation of leukemic cells. We found that miR-638 was developmentally up-regulated in cells of myeloid but not lymphoid lineage. Furthermore, significant miR-638 down-regulation was observed in primary acute myeloid leukemia (AML) blasts, whereas miR-638 expression was dramatically up-regulated in primary AML blasts and leukemic cell lines undergoing forced myeloid differentiation. These observations suggest that miR-638 might play a role in myeloid differentiation, and its dysregulation may contribute to leukemogenesis. Indeed, ectopic expression of miR-638 promoted phorbol 12-myristate 13-acetate- or all-trans-retinoic acid-induced differentiation of leukemic cell lines and primary AML blasts, whereas miR-638 inhibition caused an opposite phenotype. Consistently, miR-638 overexpression induced G1 cell cycle arrest and reduced colony formation in soft agar. Cyclin-dependent kinase 2 (CDK2) was found to be a target gene of miR-638. CDK2 inhibition phenotypically mimicked the overexpression of miR-638. Moreover, forced expression of CDK2 restored the proliferation and the colony-forming ability inhibited by miR-638. Our data suggest that miR-638 regulates proliferation and myeloid differentiation by targeting CDK2 and may serve as a novel target for leukemia therapy or marker for AML diagnosis and prognosis.
authors.affiliation: From the College of Life Sciences, Wuhan University, Wuhan, Hubei, China, 430072.
authors.forename: Yi
authors.initials: Y
authors.lastname: Lin
authors.affiliation: the Department of Hematology, Tongji Hospital of Huazhong Technology University, Wuhan, Hubei, China, 430030.
authors.forename: Dengju
authors.initials: D
authors.lastname: Li
authors.affiliation: the Department of Hematology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China, 430071, and.
authors.forename: Qing
authors.initials: Q
authors.lastname: Liang
authors.affiliation: the Department of Hematology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China, 430071, and.
authors.forename: Shangqing
authors.initials: S
authors.lastname: Liu
authors.affiliation: the Department of Hematology, Zhongnan Hospital, Wuhan University, Wuhan, Hubei, China, 430071, and.
authors.forename: Xuelan
authors.initials: X
authors.lastname: Zuo
authors.affiliation: the Department of Hematology, Jiangsu Province Hospital of Traditional Chinese Medicine (TCM), Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China, 210029.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: the Department of Hematology, Jiangsu Province Hospital of Traditional Chinese Medicine (TCM), Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China, 210029.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Sun
authors.affiliation: From the College of Life Sciences, Wuhan University, Wuhan, Hubei, China, 430072.
authors.forename: Wenxin
authors.initials: W
authors.lastname: Li
authors.affiliation: From the College of Life Sciences, Wuhan University, Wuhan, Hubei, China, 430072, guomx@whu.edu.cn.
authors.forename: Mingxiong
authors.initials: M
authors.lastname: Guo
authors.affiliation: From the College of Life Sciences, Wuhan University, Wuhan, Hubei, China, 430072, z-huang@whu.edu.cn.
authors.forename: Zan
authors.initials: Z
authors.lastname: Huang
mesh_terms: D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics / Q000378:metabolism*; D015973:Gene Expression Regulation, Leukemic; D057809:HEK293 Cells; D018922:HL-60 Cells; D006410:Hematopoiesis; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009841:Oligonucleotides / Q000235:genetics; D010641:Phenotype; D012689:Sequence Homology, Nucleic Acid; D013755:Tetradecanoylphorbol Acetate; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; C572154:MIRN638 microRNA, human; D035683:MicroRNAs; D009841:Oligonucleotides; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D013755:Tetradecanoylphorbol Acetate
keywords: Cyclin-dependent Kinase (CDK); Differentiation; Hematopoiesis; Leukemia; MicroRNA (miRNA)