title: MiR-495 is a tumor-suppressor microRNA down-regulated in MLL-rearranged leukemia.
abstract: Acute myeloid leukemia (AML) is a heterogeneous group of hematopoietic malignancies with variable response to treatment. AMLs bearing MLL (mixed lineage leukemia) rearrangements are associated with intermediate or poor survival. MicroRNAs (miRNAs), a class of small noncoding RNAs, have been postulated to be important gene expression regulators virtually in all biological processes, including leukemogenesis. Through a large-scale, genome-wide miRNA expression profiling assay of 85 human AML and 15 normal control samples, we show that among 48 miRNAs that are significantly differentially expressed between MLL- and non-MLL-rearranged AML samples, only one (miR-495) is expressed at a lower level in MLL-rearranged AML than in non-MLL-rearranged AML; meanwhile, miR-495 is also significantly down-regulated in MLL-rearranged AML samples compared with normal control samples. Through in vitro colony-forming/replating assays and in vivo bone marrow transplantation studies, we show that forced expression of miR-495 significantly inhibits MLL-fusion-mediated cell transformation in vitro and leukemogenesis in vivo. In human leukemic cells carrying MLL rearrangements, ectopic expression of miR-495 greatly inhibits cell viability and increases cell apoptosis. Furthermore, our studies demonstrate that PBX3 and MEIS1 are two direct target genes of miR-495, and forced expression of either of them can reverse the effects of miR-495 overexpression on inhibiting cell viability and promoting apoptosis of human MLL-rearranged leukemic cells. Thus, our data indicate that miR-495 likely functions as a tumor suppressor in AML with MLL rearrangements by targeting essential leukemia-related genes.
authors.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Jiang
authors.forename: Hao
authors.initials: H
authors.lastname: Huang
authors.forename: Zejuan
authors.initials: Z
authors.lastname: Li
authors.forename: Chunjiang
authors.initials: C
authors.lastname: He
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Li
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.forename: Sandeep
authors.initials: S
authors.lastname: Gurbuxani
authors.forename: Stephen
authors.initials: S
authors.lastname: Arnovitz
authors.forename: Gia-Ming
authors.initials: GM
authors.lastname: Hong
authors.forename: Colles
authors.initials: C
authors.lastname: Price
authors.forename: Haomin
authors.initials: H
authors.lastname: Ren
authors.forename: Rejani B
authors.initials: RB
authors.lastname: Kunjamma
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Neilly
authors.forename: Justin
authors.initials: J
authors.lastname: Salat
authors.forename: Mark
authors.initials: M
authors.lastname: Wunderlich
authors.forename: Robert K
authors.initials: RK
authors.lastname: Slany
authors.forename: Yanming
authors.initials: Y
authors.lastname: Zhang
authors.forename: Richard A
authors.initials: RA
authors.lastname: Larson
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Le Beau
authors.forename: James C
authors.initials: JC
authors.lastname: Mulloy
authors.forename: Janet D
authors.initials: JD
authors.lastname: Rowley
authors.forename: Jianjun
authors.initials: J
authors.lastname: Chen
mesh_terms: D000818:Animals; D001483:Base Sequence; D016022:Case-Control Studies; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D015536:Down-Regulation / Q000235:genetics*; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D015321:Gene Rearrangement / Q000235:genetics*; D052138:Genes, Neoplasm / Q000235:genetics; D056726:Genetic Association Studies; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics*; D009363:Neoplasm Proteins / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; C000616391:MEIS1 protein, human; C577768:MIRN495 microRNA, human; C000616392:Meis1 protein, mouse; D035683:MicroRNAs; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; C090466:proto-oncogene protein Pbx3; D051788:Myeloid-Lymphoid Leukemia Protein