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.