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Acute Myeloid Leukemia
Transforming activities of the NUP98-KMT2A fusion gene associated with myelodysplasia and acute myeloid leukemia
Ferrata Storti Foundation
Haematologica 2020 Volume 105(7):1857-1867
James N. Fisher,1,2* Angeliki Thanasopoulou,1,2* Sabine Juge,1,2 Alexandar Tzankov,3 Frederik O. Bagger,1,2 Max A. Mendez,1,2 Antoine H.F.M. Peters4,5 and Juerg Schwaller1,2
1University Children’s Hospital Basel (UKBB); 2Department of Biomedicine, University of Basel; 3Institute for Pathology, University of Basel; 4Faculty of Sciences, University of Basel and 5Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
*JNF and ATh contributed equally as co-first authors.
ABSTRACT
Inv(11)(p15q23), found in myelodysplastic syndromes and acute myeloid leukemia, leads to expression of a fusion protein consisting of the N-ter- minal of nucleoporin 98 (NUP98) and the majority of the lysine methyl- transferase 2A (KMT2A). 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 these mice developed signs of dis- ease, with anemia and reduced bone marrow cellularity, increased white blood cell numbers, extramedullary hematopoiesis, and multilineage dyspla- sia. Additionally, induction of iNUP98-KMT2A led to elevated lineage mark- er-negative Sca-1+ c-Kit+ cell numbers in the bone marrow, which outcom- peted wildtype cells in repopulation assays. Six iNUP98-KMT2A mice devel- oped transplantable acute myeloid leukemia with leukemic blasts infiltrating multiple organs. Notably, as reported for patients, iNUP98-KMT2A leukemic blasts did not express increased levels of the HoxA-B-C gene clus- ter, 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 the 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. In summary, we demonstrate that iNUP98-KMT2A has in vivo transforming activity and interferes with cell cycle progression rather than primarily blocking differentiation.
Introduction
The gene encoding the 98 kDa nuclear pore protein (NUP98) is recurrently involved in chromosomal translocations associated with various hematologic malignancies. Most of these translocations result in the expression of fusion genes comprising the N-terminal phenylalanine-glycine (FG)-repeats of NUP98 fused to a large group of different partners of which the homeobox family of transcription factors (such as HOXA9 or HOXD13) or non-homeobox epigenetic regulators are a part.1,2 Like NUP98, the lysine methyltransferase KMT2A, also referred to as “mixed lineage leukemia” (MLL) gene, encoding for a SET-domain histone H3K4 methyltransferase is a recurrent target of leukemia-associated chromosomal rearrangements. These generally lead to expression of fusion transcripts that con- tain the amino-terminal moiety of KMT2A fused to different partners, of which AF4, AF9, ENL and AF10 are among the most prevalent of the currently more than 70 known.3,4 Several KMT2A fusions have been shown to be hematopoietic onco- genes, which phenocopy the disease in vivo when expressed in murine bone mar-
Correspondence:
JUERG SCHWALLER
j.schwaller@unibas.ch
Received: March 1, 2019.
Accepted: September 24, 2019. Pre-published: September 26, 2019.
doi:10.3324/haematol.2019.219188
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