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Blood, 29 January 2009, Vol. 113, No. 5, pp. 1075-1085. Prepublished online as a Blood First Edition Paper on October 23, 2008; DOI 10.1182/blood-2008-03-144436. This Article Full Text (PDF) Supplemental Tables and Figures All Versions of this Article: blood-2008-03-144436v1 113/5/1075    most recent Alert me when this article is cited Alert me if a correction is posted 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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Yin, B. Articles by Largaespada, D. A Search for Related Content PubMed PubMed Citation Articles by Yin, B. Articles by Largaespada, D. A Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 12, 2008 Accepted October 14, 2008 A retroviral mutagenesis screen reveals strong cooperation between Bcl11a overexpression and loss of the Nf1 tumor suppressor gene Bin Yin, Ruud Delwel, Peter J Valk, Margaret R Wallace, Mignon L. Loh, Kevin M Shannon, and David A Largaespada* Department of Genetics, Cell Biology and Development, Masonic Cancer Center, University of Minnesota, Minneapolis, MN, United States Department of Hematology, Erasmus University Medical Centre, Rotterdam, Netherlands Department of Molecular Genetics and Microbiology, Center for Mammalian Genetics, University of Florida College of Medicine, Gainesville, FL, United States Department of Pediatrics, University of California, San Francisco, CA, United States * Corresponding author; email: larga002{at}tc.umn.edu. NF1 inactivation occurs in specific human cancers, including juvenile myelomononcytic leukemia (JMML), an aggressive myeloproliferative disorder of childhood. However, evidence suggests that Nf1 loss alone does not cause leukemia. We, therefore, hypothesized that inactivation of the Nf1 tumor suppressor gene requires cooperating mutations to cause acute leukemia. To search for candidate genes that cooperate with Nf1-deficiency in leukemogenesis, we performed a forward genetic screen using retroviral insertion mutagenesis in Nf1 mutant mice. We identified 43 common proviral insertion sites that contain candidate genes involved in leukemogenesis. One of these genes, Bcl11a, confers a growth advantage in cultured Nf1 mutant hematopoietic cells, and causes early onset of leukemia of either myeloid or lymphoid lineage in mice when expressed in Nf1-deficient bone marrow. Bcl11a-expressing cells display compromised p21Cip1 induction, suggesting that Bcl11a's oncogenic effects are mediated, in part, through suppression of p21Cip1. Importantly, Bcl11a is expressed in human chronic myelomonocytic leukemia and JMML samples. A subset of AML patients, who had poor outcomes, out of sixteen clusters, displayed high levels of BCL11A in leukemic cells. These findings suggest that deregulated Bcl11a cooperates with Nf1 in leukemogenesis, and a therapeutic strategy targeting the BCL11A pathway may prove beneficial in the treatment of leukemia. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: B. A. Cutts, A.-K. M. Sjogren, K. M. E. Andersson, A. M. Wahlstrom, C. Karlsson, B. Swolin, and M. O. Bergo Nf1 deficiency cooperates with oncogenic K-RAS to induce acute myeloid leukemia in mice Blood, October 22, 2009; 114(17): 3629 - 3632. [Abstract] [Full Text] [PDF] J. Koenigsmann, C. Rudolph, S. Sander, O. Kershaw, A. D. Gruber, L. Bullinger, B. Schlegelberger, and D. Carstanjen Nf1 haploinsufficiency and Icsbp deficiency synergize in the development of leukemias Blood, May 7, 2009; 113(19): 4690 - 4701. [Abstract] [Full Text] [PDF]

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