Alterations in 3D-DNA architecture drive unique leukemic profiles in IDH1- and DNMT3A-mutant acute myeloid leukemia

Acute myeloid leukemia (AML) is characterized by complex molecular alterations including mutations in epigenetic regulators such as IDH1 and DNMT3A , which are associated with globally altered DNA methylation affecting gene transcription, treatment choices, and outcomes. Additionally, IDH1 mutations are linked to changes in DNA-loop formation leading to oncogene upregulation. Here, we assessed 3D-DNA conformational changes in IDH1- and DNMT3A -mutated (mut) AML on a genome-wide scale as a global driver of leukemic signaling to identify novel therapeutic vulnerabilities. Using a cellular model with either IDH1 p.R132H or DNMT3A p.R882H mutation and primary AML samples, we analyzed mutation-specific 3D-DNA architecture by chromatin-conformation-capture (HiC) and transcriptional alterations by RNA sequencing. We identified both shared and distinct changes in compartmentalization and underlying DNA-loop formation in both DNMT3A- and IDH1 -mut AML, which were linked to differential gene expression, supporting that 3D-genome architecture broadly influences transcription. Thereby, loop-mediated upregulation of IGF1R was identified in IDH1 -mut AML, corresponding to specific sensitivity to IGF1R inhibitor BMS-754807 as mono- and combination therapy with ivosidenib, while DNMT3A -mut AML exhibited sensitivity to p38/MAPK inhibitor ralimetinib. Our data present a comprehensive map of global 3D-DNA alterations associated with IDH1 - and DNMT3A mutations as a basis for further assessment of novel therapeutic strategies for both AML entities.