MN1 overexpression induces acute myeloid leukemia in mice and predictsATRA resistance in patients withAML

Overexpression of wild-type MN1 is a negative prognostic factor in patients with acute myeloid leukemia (AML) with nor- mal cytogenetics. We evaluated whether MN1 plays a functional role in leukemo- genesis. We demonstrate using retroviral gene transfer and bone marrow (BM) transplantation that MN1 overexpression rapidly induces lethal AML in mice. Inser- tional mutagenesis and chromosomal in- stability were ruled out as secondary ab- errations. MN1 increased resistance to all-trans retinoic acid (ATRA)-induced cell-cycle arrest and differentiation by more than 3000-fold in vitro. The differen- tiation block could be released by fusion of a transcriptional activator (VP16) to MN1 without affecting the ability to immor- talize 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 treat- ment protocol AMLHD98-B. Strikingly, pa- tients with low MN1 expression who re- ceived ATRA had a significantly prolonged event-free (P.008) and overall (P.04) survival compared with patients with ei- ther low MN1 expression and no ATRA, or high MN1 expression with or without ATRA. MN1 is a unique oncogene in hema- topoiesis that both promotes proliferation/ self-renewal and blocks differentiation, and may become useful as a predictive marker in AML treatment. (Blood. 2007; 110:1639-1647)