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Blood, 1 September 2007, Vol. 110, No. 5, pp. 1639-1647. Prepublished online as a Blood First Edition Paper on May 9, 2007; DOI 10.1182/blood-2007-03-080523. This Article Full Text Full Text (PDF) Supplemental Tables Supplemental Figures All Versions of this Article: blood-2007-03-080523v1 110/5/1639    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 HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Heuser, M. Articles by Humphries, R. K. Search for Related Content PubMed PubMed Citation Articles by Heuser, M. Articles by Humphries, R. K. Related Collections Neoplasia Gene Expression Clinical Trials and Observations Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA MN1 overexpression induces acute myeloid leukemia in mice and predicts ATRA resistance in patients with AML Michael Heuser1, Bob Argiropoulos1, Florian Kuchenbauer1, Eric Yung1, Jessica Piper1, Stephen Fung1, Richard F. Schlenk2, Konstanze Dohner2, Tanja Hinrichsen3, Cornelia Rudolph3, Axel Schambach4, Christopher Baum4, Brigitte Schlegelberger3, Hartmut Dohner2, Arnold Ganser5, and R. Keith Humphries1 1 Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, BC, Canada; 2 Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany; 3 Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany; 4 Department of Experimental Hematology, Hannover Medical School, Hannover, Germany; 5 Department of Hematology, Hemostasis and Oncology, Hannover Medical School, Hannover, Germany Overexpression of wild-type MN1 is a negative prognostic factor in patients with acute myeloid leukemia (AML) with normal cytogenetics. We evaluated whether MN1 plays a functional role in leukemogenesis. We demonstrate using retroviral gene transfer and bone marrow (BM) transplantation that MN1 overexpression rapidly induces lethal AML in mice. Insertional mutagenesis and chromosomal instability were ruled out as secondary aberrations. MN1 increased resistance to all-trans retinoic acid (ATRA)–induced cell-cycle arrest and differentiation by more than 3000-fold in vitro. The differentiation block could be released by fusion of a transcriptional activator (VP16) to MN1 without affecting the ability to immortalize BM cells, suggesting that MN1 blocks differentiation by transcriptional repression. We then evaluated whether MN1 expression levels in patients with AML (excluding M3-AML) correlated with resistance to ATRA treatment in elderly patients uniformly treated within treatment protocol AMLHD98-B. Strikingly, patients with low MN1 expression who received ATRA had a significantly prolonged event-free (P = .008) and overall (P = .04) survival compared with patients with either low MN1 expression and no ATRA, or high MN1 expression with or without ATRA. MN1 is a unique oncogene in hematopoiesis that both promotes proliferation/self-renewal and blocks differentiation, and may become useful as a predictive marker in AML treatment. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Treating AML with ATRA? Beware MN1! Gerard C. Grosveld Blood 2007 110: 1401-1402. [Full Text] [PDF] This article has been cited by other articles: X. Zhang, D. R. Dowd, M. C. Moore, T. A. Kranenburg, M. A. Meester-Smoor, E. C. Zwarthoff, and P. N. MacDonald Meningioma 1 Is Required for Appropriate Osteoblast Proliferation, Motility, Differentiation, and Function J. Biol. Chem., July 3, 2009; 284(27): 18174 - 18183. [Abstract] [Full Text] [PDF] C. Langer, G. Marcucci, K. B. Holland, M. D. Radmacher, K. Maharry, P. Paschka, S. P. Whitman, K. Mrozek, C. D. Baldus, R. Vij, et al. Prognostic Importance of MN1 Transcript Levels, and Biologic Insights From MN1-Associated Gene and MicroRNA Expression Signatures in Cytogenetically Normal Acute Myeloid Leukemia: A Cancer and Leukemia Group B Study J. Clin. Oncol., July 1, 2009; 27(19): 3198 - 3204. [Abstract] [Full Text] [PDF] M. Heuser, D. B. Yap, M. Leung, T. R. de Algara, A. Tafech, S. McKinney, J. Dixon, R. Thresher, B. Colledge, M. Carlton, et al. Loss of Mll5 results in pleiotropic hematopoietic defects, reduced neutrophil immune function, and extreme sensitivity to DNA demethylation Blood, February 12, 2009; 113(7): 1432 - 1443. [Abstract] [Full Text] [PDF] S. Imren, M. Heuser, L.-Y. Chen, G. Edin, C. J. Eaves, and R. K. Humphries MN1 Overexpression Promotes Proliferation and Self-Renewal of Primitive Normal Human Hematopoietic Cells Blood (ASH Annual Meeting Abstracts), November 16, 2008; 112(11): 681 - 681. [Abstract] C. Guy, A. Gilkes, R. Gale, D. C. Linch, R. Hills, and A. K. 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