Co-mutation of asxl1 and IDH2R172K enhances leukemogenesis and correlates with epigenetic activation of MAPK and AP-1

Co-mutations of asxl1 and IDH2 are associated with aggressive acute myeloid leukemia (AML), yet the underlying mechanisms have remained poorly understood. We generated a zebrafish model combining asxl1 mutation 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, downregulation of tet2 expression, and showed global changes in methylation profiles. Genes pertaining to MAPK and AP-1 pathway were upregulated, associated with NADPH oxidase (NOX) expression and an increase in reactive oxygen species (ROS). Single-cell RNA-sequencing confirmed differentiation arrest in HSC-progenitor with activation of MAPK and AP-1 signaling. The double mutants showed resistance to the 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 and AP-1 pathway. Our findings underscored an epigenetic-metabolic signaling circuit driving leukemogenesis and revealed novel therapeutic strategies for this AML subtype.