FLT3^ITD drives context-specific changes in cell identity and variable interferon dependence during AML initiation

Acute myeloid leukemia (AML) initiation requires multiple rate-limiting mutations to cooperatively reprogram progenitor cell identity. For example, FLT3 internal tandem duplication (FLT3^ITD) mutations cooperate with a variety of different initiating mutations to reprogram myeloid progenitor fate. These initiating mutations often skew toward either pediatric or adult AML patient populations, though FLT3^ITD itself occurs at similar frequencies in both age groups. This raises the question of whether FLT3^ITD might induce distinct transcriptional programs and unmask distinct therapeutic vulnerabilities when paired with pediatric, as opposed to adult AML-initiating mutations. To explore this possibility, we compared AML evolution in mice that carried Flt3^ITD/NUP98-HOXD13 (NHD13) or Flt3^ITD/Runx1^DEL mutation pairs, which are respectively most common in pediatric and adult AML. Single-cell analyses and epigenome profiling revealed distinct interactions between Flt3^ITD and its cooperating mutations. Whereas Flt3^ITD and Flt3^ITD/Runx1^DEL caused aberrant expansion of myeloid progenitors, Flt3^ITD/NHD13 drove the emergence of a pre-AML population that did not resemble normal hematopoietic progenitors. Differences between Flt3^ITD/Runx1^DEL and Flt3^ITD/NHD13 cooperative target gene expression extended to fully transformed AML as well. Flt3^ITD/NHD13 cooperative target genes were enriched in human NUP98-translocated AML. Flt3^ITD/NHD13 selectively hijacked type I interferon signaling to drive expansion of the pre-AML population. Blocking interferon signaling delayed AML initiation and extended survival. Thus, common AML driver mutations, such as FLT3^ITD, can coopt different mechanisms of transformation in different genetic contexts. Furthermore, pediatric-biased NUP98 fusions convey actionable interferon dependence.