NUP98::NSD1 and FLT3-ITD collaborate to generate acute myeloid leukemia

Abstract Nucleoporin 98 (NUP98) fusion genes and FMS-related tyrosine kinase 3 gene (FLT3) internal tandem duplications (ITDs) are recurrent events in patients with acute myeloid leukemia (AML). The NUP98::NSD1 fusion, which joins the amino terminal portion of NUP98 to the carboxy terminal portion of NSD1 (Nuclear receptor-binding SET Domain 1) is the most common NUP98 fusion in human AML. AML patients with NUP98::NSD1 fusion typically also have a FLT3-ITD mutation, and the combination of these two oncoproteins results in a poor prognosis. We established NUP98::NSD1 transgenic mice as an in vivo model. Although the penetrance of AML in mice that expressed a NUP98::NSD1 fusion was low, the incidence of AML increased dramatically when accompanied by a FLT3-ITD mutation. Gene expression profiling showed that murine NUP98::NSD1/FLT3-ITD AML were myelomonocytic, with an expression profile similar to human NUP98::NSD1 AML. Also similar to human AML, the wild type Flt3 allele was frequently lost in murine NUP98::NSD1/FLT3-ITD AML. Whole exome sequencing of NUP98::NSD1/FLT3-ITD AML revealed few Tier 1 somatic mutations, suggesting that the NUP98::NSD1 fusion protein and FLT3-ITD may be sufficient for leukemogenesis. This study demonstrates that the NUP98::NSD1 fusion gene is leukemogenic in vivo, and provides a model for pre-clinical studies.