Co-mutation of asxl1 and IDH2R172K induces leukemogenesis via epigenetic activation of MAPK /AP-1 pathway in leukemic stem cells

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 increase in reactive oxygen species (ROS). Single-cell RNA-sequencing confirmed differentiation arrest in HSC-progenitor with activation of MAPK/AP-1 signaling. The double mutants showed resistance to IDH2 inhibitor but were sensitive to ROS or DNA methylation targeting.