Comutation of asxl1 and IDH2R172K enhances leukemogenesis and correlates with epigenetic activation of MAPK and AP-1 in zebrafish.

Abstract

Abstract: Comutations of addition of sex combs-like 1 (asxl1) and isocitrate dehydrogenases 2 (IDH2) are associated with aggressive acute myeloid leukemia (AML), yet the underlying mechanisms have remained poorly understood. We generated a zebrafish model combining an asxl1 mutation and an IDH2R172K mutation that recapitulates the clinicopathological and molecular features of high-risk AML with differentiation blockade and reduced animal survival. The double mutants exhibited promoter hypermethylation, downregulation of tet2 expression, and global changes in methylation profiles. Genes pertaining to MAPK and activator protein-1 (AP-1) pathways were upregulated, which was associated with reduced NAD phosphate oxidase expression and an increase in reactive oxygen species (ROS). Single-cell RNA sequencing confirmed differentiation arrest in hematopoietic stem and progenitor cells, 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 in human AML carrying comutation of ASXL1/IDH2 also showed activation of the MAPK and AP-1 pathways. Our findings underscore an epigenetic-metabolic signaling circuit driving leukemogenesis and reveal novel therapeutic strategies for this AML subtype.