title: Regulation of mir-196b by MLL and its overexpression by MLL fusions contributes to immortalization.
abstract: Chromosomal translocations involving the Mixed Lineage Leukemia (MLL) gene produce chimeric proteins that cause abnormal expression of a subset of HOX genes and leukemia development. Here, we show that MLL normally regulates expression of mir-196b, a hematopoietic microRNA located within the HoxA cluster, in a pattern similar to that of the surrounding 5' Hox genes, Hoxa9 and Hoxa10, during embryonic stem (ES) cell differentiation. Within the hematopoietic lineage, mir-196b is most abundant in short-term hematopoietic stem cells and is down-regulated in more differentiated hematopoietic cells. Leukemogenic MLL fusion proteins cause overexpression of mir-196b, while treatment of MLL-AF9 transformed bone marrow cells with mir-196-specific antagomir abrogates their replating potential in methylcellulose. This demonstrates that mir-196b function is necessary for MLL fusion-mediated immortalization. Furthermore, overexpression of mir-196b was found specifically in patients with MLL associated leukemias as determined from analysis of 55 primary leukemia samples. Overexpression of mir-196b in bone marrow progenitor cells leads to increased proliferative capacity and survival, as well as a partial block in differentiation. Our results suggest a mechanism whereby increased expression of mir-196b by MLL fusion proteins significantly contributes to leukemia development.
authors.affiliation: Molecular Biology Program, Loyola University Medical Center, Maywood, IL, USA.
authors.forename: Relja
authors.initials: R
authors.lastname: Popovic
authors.forename: Laurie E
authors.initials: LE
authors.lastname: Riesbeck
authors.forename: Chinavenmeni S
authors.initials: CS
authors.lastname: Velu
authors.forename: Aditya
authors.initials: A
authors.lastname: Chaubey
authors.forename: Jiwang
authors.initials: J
authors.lastname: Zhang
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Achille
authors.forename: Frank E
authors.initials: FE
authors.lastname: Erfurth
authors.forename: Katherine
authors.initials: K
authors.lastname: Eaton
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.forename: H Leighton
authors.initials: HL
authors.lastname: Grimes
authors.forename: Jianjun
authors.initials: J
authors.lastname: Chen
authors.forename: Janet D
authors.initials: JD
authors.lastname: Rowley
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Zeleznik-Le
mesh_terms: D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D005786:Gene Expression Regulation / Q000502:physiology; D011495:Histone-Lysine N-Methyltransferase; D007938:Leukemia / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000502:physiology; D008969:Molecular Sequence Data; D051788:Myeloid-Lymphoid Leukemia Protein / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012689:Sequence Homology, Nucleic Acid; D015854:Up-Regulation / Q000502:physiology
chemical_list: C542543:MIRN196 microRNA, human; D035683:MicroRNAs; D011993:Recombinant Fusion Proteins; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse