Supporting data for “Activation of MAPK/AP-1 pathway mediates asxl1 and IDH2R172K mutated leukemogenesis”

Co-occurring mutations of asxl1 and IDH2 are associated with aggressive acute myeloid leukemia (AML), yet the mechanisms underlying their synergy remain poorly understood. We generated a zebrafish model combining asxl1 loss and IDH2R172K mutation that recapitulates the clinicopathologic and molecular features of high-risk AML with differentiation blockade and reduced animal survival. The double mutant exhibited promoter hypermethylation of tet2, leading to its downregulation and global changes in methylation profiles. Genes pertaining to MAPK/AP-1 pathway were upregulated, leading to NADPH oxidase (NOX) expression and an increase in reactive oxygen species (ROS). Single-cell RNA-sequencing confirmed differentiation arrest in HSC-progenitor with evidence of activated ROS-MAPK/AP-1 signaling. The double mutants showed resistance to IDH2 inhibitor but were sensitive to ROS or DNA methylation targeting. In silico analysis of gene expression of human AML carrying co-mutation of ASXL1/IDH2 also showed activation of the MAPK/AP-1 pathway. Our findings underscored an epigenetic-metabolic signaling circuit driving leukemogenesis and revealed novel therapeutic strategies for this AML subtype.