Chromosomal rearrangements of the 11p15 locus have been identified in hematopoietic malignancies, resulting in translocations involving the N-terminal portion of the nucleoporin gene NUP98. Fifteen different fusion partner genes have been identified for NUP98, and more than one half of these are homeobox transcription factors. By contrast, the NUP98 fusion partner in t(11;20) is Topoisomerase I (TOP1), a catalytic enzyme recognized for its key role in relaxing supercoiled DNA. We now show that retrovirally engineered expression of NUP98-TOP1 in murine bone marrow confers a potent in vitro growth advantage and a block in differentiation in hematopoietic precursors, evidenced by a competitive growth advantage in liquid culture, increased replating efficient of colony-forming cells (CFCs), and a marked increase in spleen colonyforming cell output. Moreover, in a murine bone marrow transplantation model, NUP98-TOP1 expression led to a lethal, transplantable leukemia characterized by extremely high white cell counts, splenomegaly, and mild anemia. Strikingly, a mutation to a TOP1 site to inactivate the isomerase activity essentially left unaltered the growth-promoting and leukemogenic effects of NUP98-TOP1. These findings, together with similar biologic effects reported for NUP98-HOX fusions, suggest unexpected, overlapping functions of NUP98 fusion genes, perhaps related to common DNA binding properties. IntroductionA heterogenous group of hematopoietic malignancies has been described that are characterized by chromosomal translocations that create fusion genes involving the N-terminal portion of the nucleoporin gene, NUP98, on chromosome 11p15. 1 To date, 15 distinct fusion partners have been identified in NUP98 translocations. The most frequently observed fusion partners for NUP98 belong to the homeobox family of transcription factors and include HOXA9, 2,3 HOXD13, 4 HOXD11, 5 HOXA11, 6 HOXA13, 7,8 HOXC11,9 and HOXC13 10 as well as the nonclustered homeobox gene PMX1. 11 Recent studies in murine model systems have clearly demonstrated that both NUP98-HOXA9 and NUP98-HOXD13 play a causal and overt role in the pathogenesis of leukemia. 12,13 Furthermore, the disease onset can be greatly accelerated in these models by coexpression of the NUP98-HOX fusion gene and the HOX co-factor Meis1. These reports are consistent with the observations that HOX genes play key roles in the regulation of hematopoiesis and that overexpression of select HOX genes (eg, HOXA10, 14 HOXB3 15 ) lead to leukemia.In addition to the HOX genes, 7 "variant" partner genes that are associated with a wide range of biologic functions have been identified in fusion with NUP98 in hematopoietic malignancies. These include DDX10, 16,17 RAP1GDS1,18,19 Topoisomerase I, 20 LEDGF, 21 NSD1, 22 NSD3, 23 and Adducin 3. 24 These NUP98 fusion partner genes are diverse in function and, in contrast to the HOX fusion partners, are not known to have a specific or unique function in hematopoiesis.An intriguing example of one such non-HOX partner is Topoisomerase I (...

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