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Blood, 2 April 2009, Vol. 113, No. 14, pp. 3314-3322. Prepublished online as a Blood First Edition Paper on February 2, 2009; DOI 10.1182/blood-2008-04-154310. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2008-04-154310v1 113/14/3314    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Popovic, R. Articles by Zeleznik-Le, N. J. Search for Related Content PubMed PubMed Citation Articles by Popovic, R. Articles by Zeleznik-Le, N. J. Related Collections Hematopoiesis and Stem Cells Myeloid Neoplasia Lymphoid Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  MYELOID NEOPLASIA Regulation of mir-196b by MLL and its overexpression by MLL fusions contributes to immortalization Relja Popovic1, Laurie E. Riesbeck1, Chinavenmeni S. Velu2, Aditya Chaubey2, Jiwang Zhang3, Nicholas J. Achille3, Frank E. Erfurth3, Katherine Eaton3, Jun Lu4, H. Leighton Grimes2, Jianjun Chen5, Janet D. Rowley5, and Nancy J. Zeleznik-Le1,3,6 1 Molecular Biology Program, Loyola University Medical Center, Maywood, IL; 2 Division of Immunobiology, Cincinnati Children's Hospital Medical Center, OH; 3 Oncology Institute, Loyola University Medical Center, Maywood, IL; 4 Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA; 5 Department of Medicine, University of Chicago, IL; and 6 Department of Medicine, Loyola University Medical Center, Maywood, IL 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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