Activating mutations remodeled the chromatin accessibility landscape to drive distinct regulatory networks in KMT2A-rearranged acute leukemia

Activating FLT3 and RAS mutations are common in KMT2A-rearrangement (KMT2A-r) leukemia, but their functions in remodeling the chromatin accessibility is unknow. Using a retroviral acute myeloid leukemia (AML) mouse model driven by KMT2A::MLLT3, we show that FLT3/ITD, FLT3/N676K, and NRAS/G12D rewired the chromatin accessibility landscape and associated transcriptional networks. FLT3/N676K and NRAS/G12D mutations resulted in similar networks which were distinct from those mediated by FLT3/ITD. Motif analysis revealed that the AP-1 family transcription factors had a role in KMT2A::MLLT3 leukemia with FLT3/N676K and NRAS/G12D, whereas RUNX1/2 and Stat5a/Stat5b were active in the presence of FLT3/ITD. Further, transcriptional programs related with stemness, activation of T-cells and negative regulation of NK-cells were activated in the presence of NRAS/G12D and FLT3/N676K. Taken together, activating mutations established mutation-specific changes in the epigenetic landscape that led to changes in the transcriptional programs driven by specific transcription factors. 15 mice with acute myeloid leukemia (AML) driven by KMT2A::MLLT3-mCherry and either of FLT3/ITD-GFP (n=4), FLT3/N676K-GFP (n=4), NRAS/G12D-GFP (n=3), or control vector (n=4).