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 Flt3ITD 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 pro-genitors. 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.