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

Transforming activities of the NUP98-KMT2A fusion gene associated with myelodysplasia and acute myeloid leukemia. Haematologica. 2019 Sep 26;: Authors: Fisher JN, Thanasopoulou A, Juge S, Tzankov A, Bagger FO, Mendez MA, Peters AHFM, Schwaller J Abstract 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 iN...
Source: Haematologica - Category: Hematology Authors: Tags: Haematologica Source Type: research