Activating mutations remodel the chromatin accessibility landscape to drive distinct regulatory networks in -rearranged acute leukemia.

Activating and mutations commonly occur in leukemia with -gene rearrangements (-r). However, how these mutations cooperate with the -r to remodel the epigenetic landscape is unknown. Using a retroviral acute myeloid leukemia (AML) mouse model driven by , we show that , , and remodeled the chromatin accessibility landscape and associated transcriptional networks. Although the activating mutations shared a common core of chromatin changes, each mutation exhibits unique profiles with most opened peaks associating with enhancers in intronic or intergenic regions. Specifically, and rewired similar chromatin and transcriptional networks, distinct from those mediated by . Motif analysis uncovered a role for the AP-1 family of transcription factors in leukemia with and , whereas Runx1 and Stat5a/Stat5b were active in the presence of . Furthermore, transcriptional programs linked to immune cell regulation were activated in -r AML expressing or , and the expression of NKG2D-ligands on -r cells rendered them sensitive to CAR T cell-mediated killing. Human -r AML cells could be pharmacologically sensitized to NKG2D-CAR T cells by treatment with the histone deacetylase inhibitor LBH589 (panobinostat) which caused upregulation of NKG2D-ligand levels. Co-treatment with LBH589 and NKG2D-CAR T cells enabled robust AML cell killing, and the strongest effect was observed for cells expressing . Finally, the results were validated and extended to acute leukemia in infancy. Combined, activating mutations induced mutation-specific changes in the epigenetic landscape, leading to changes in transcriptional programs orchestrated by specific transcription factor networks.