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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.
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Submitted March 16, 2007
Accepted April 28, 2007
MN1 overexpression induces acute myeloid leukemia in mice and predicts ATRA resistance in AML patients
Michael Heuser, Bob Argiropoulos, Florian Kuchenbauer, Eric Yung, Jessica Piper, Stephen Fung, Richard F. Schlenk, Konstanze Dohner, Tanja Hinrichsen, Cornelia Rudolph, Axel Schambach, Christopher Baum, Brigitte Schlegelberger, Hartmut Dohner, Arnold Ganser, and R. Keith Humphries*
Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada
Department of Internal Medicine III, University Hospital of Ulm, Ulm, Germany
Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany
Department of Experimental Hematology, Hannover Medical School, Hannover, Germany
Department of Hematology, Hemostasis and Oncology, Hannover Medical School, Hannover, Germany
* Corresponding author; email: khumphri{at}bccrc.ca.
Overexpression of wild-type MN1 is a negative prognostic factor in acute myeloid leukemia (AML) patients with normal cytogenetics. We evaluated whether MN1 plays a functional role in leukemogenesis. We demonstrate using retroviral gene transfer and bone marrow 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 >3,000-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 AML patients (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 survival (P=.04) compared to 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.
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