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creates an active gene transcription elongation environ- ment at KMT2A-X target genes (e.g. HOX genes), which is reinforced by the recognition of acetylated lysines on histones at important oncogene loci (e.g. MYC) by the BET proteins including BRD4. Based on these dependen- cies, small molecule inhibitors of DOT1L, of BRD4 and of the interaction between KMT2A and MEN1 have been developed.6-8
Other alterations of KMT2A function are observed. In some instances reciprocal X-KMT2A fusions were shown to contribute to leukemogenesis in murine model (e.g. AFF1-KMT2A cooperation with KMT2A-AFF19). KMT2A partial tandem duplications (KMT2A-PTD) are also found in AML and both murine modeling and human genetics indicate that KMT2A-PTD requires additional mutations to induce bona fide leukemia.10,11
Wildtype NUP98 is part of the nuclear pore complex, a large structure of ~30 proteins at the nuclear membrane which provides a bidirectional channel allowing small ions and peptides to diffuse and larger molecules (mRNA and proteins) to be actively transported by carriers.
NUP98 is different from other nucleoporins as it contains multiple GLFG repeats allowing interaction with CREBBP/EP300 and it can be found throughout the nucle- us. Nup98 was reported to be involved, together with Rae, in cell cycle progression and mitotic spindle regula- tion.12 Notably, NUP98 is found at sites of actively tran- scribed genes presenting the H3K4me3 mark and is involved in cell cycle and development.13 NUP98 is also involved with wildtype KMT2A and NSL in complexes regulating HOX gene expression.14
In leukemia, NUP98 is recurrently fused with over 30 different partners (including NSD1, KDM5A, but also homeodomain proteins such as HOXA9, HOXC11, HOXD11 or HOXD13). These fusions (termed NUP98-X here) result from chromosomal alterations that are fre- quently undetected by conventional cytogenetics due to the location of the NUP98 gene close to the telomere of the short arm of chromosome 11 (11p15).15,16 In the case of chimeras between NUP98 and homeodomain proteins, the GLFG repeats of NUP98 generally replace the transac- tivation domain. To date, all NUP98-X fusions have been
Figure 1. Molecular mechanisms associated with KMT2A-X and NUP98-KMT2A fusions. Schematic representation of the functional domains of wildtype KMT2A, KMT2A-X (where X corresponds to the fusion partners), and NUP98-KMT2A and the molecular mechanisms associated with leukemic transformation. While KMT2A- X fusions are associated with high expression (High) of HOX genes and MYC, NUP98-KMT2A is associated with low HOX genes (Low) and its regulation on MYC expres- sion remains unknown (?). In mice, NUP98-KMT2A transformation is associated with high expression of cell cycle-associated genes (e.g. Sirt1, Rbl2 and Tert2). Therapeutic targeting developed for KMT2A-X leukemia includes MEN1, DOT1L and BRD4 inhibitors. Whether small-molecule inhibitors of SET domain or TASPASE 1 activities would be efficient in NUP98-KMT2A leukemia is unknown. AT: AT-hook domain; SNL: speckled nuclear localization domains; MBD: MENIN 1-binding domain; PHD: plant homeodomain finger domain; BD: bromodomain; FYRN and FYRC: phenylalanine/tyrosine-rich-N- and C-terminal domains; TAD: transactivation domain; SET: SET methyltransferase activity domain.
haematologica | 2020; 105(7)