Transforming activities of the NUP98-KMT2A fusion gene associated with myelodysplasia and acute myeloid leukemia

Inv(11)(p15q23) found in myelodysplastic syndromes and acute myeloid leukemia leads to expression of a fusion protein consisting of the N-terminal of nucleoporin 98 (NUP98) and the majority of the lysine methyltransferase 2A (KMT2A) transcript. To explore the transforming potential of this fusion we established inducible iNUP98-KMT2A transgenic mice. After a median latency of 80 weeks, over 90% of induced mice developed signs of disease, including anemia and reduced bone marrow cellularity, increased white blood cell numbers, extramedullary hematopoiesis, and multi-lineage dysplasia. Additionally, induction of iNUP98-KMT2A lead to elevated lineage marker-negative Sca-1+ c-Kit+ cell numbers in the bone marrow, which outcompeted wild type cells in repopulation assays. Six iNUP98-KMT2A mice developed transplantable acute myeloid leukemia with leukemic blasts infiltrating multiple organs. Notably, as reported for patients, iNUP98-MLL leukemic blasts did not express increased levels of the HoxA-B-C gene cluster, and in contrast to KMT2A-AF9 leukemic cells, the cells were resistant to pharmacological targeting of menin and BET family proteins by MI-2-2 or JQ1 respectively. Expression of iNUP98-KMT2A in mouse embryonic fibroblasts led to an accumulation of cells in G1 phase, and abrogated replicative senescence. In bone marrow-derived hematopoietic progenitors, iNUP98-KMT2A expression similarly resulted in increased cell numbers in G1 phase of the cell cycle, with aberrant gene expression of Sirt1, Tert, Rbl2, Twist1, Vim, and Prkcd, mimicking that seen in mouse embryonic fibroblasts. Collectively, we demonstrate that iNUP98-KMT2A has in vivo transforming activity and interferes with cell cycle progression rather than primarily blocking differentiation.