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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.
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Submitted April 30, 2008
Accepted January 8, 2009
Regulation of mir-196b by MLL and its overexpression by MLL fusions contributes to immortalization
Relja Popovic, Laurie E. Riesbeck, Chinavenmeni S. Velu, Aditya Chaubey, Jiwang Zhang, Nicholas J. Achille, Frank E. Erfurth, Katherine Eaton, Jun Lu, H. Leighton Grimes, Jianjun Chen, Janet D. Rowley, and Nancy J. Zeleznik-Le*
Molecular Biology Program, Loyola University Medical Center, Maywood, IL, United States
Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States
Oncology Institute, Loyola University Medical Center, Maywood, IL, United States
Broad Institute of MIT and Harvard, Cambridge, MA, United States
Department of Medicine, University of Chicago, Chicago, IL, United States
Department of Medicine, Loyola University Medical Center, Maywood, IL, United States
* Corresponding author; email: nzelezn{at}lumc.edu.
Chromosomal translocations involving the MLL gene produce chimeric proteins which 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 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.
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