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Additionally,\n                    <jats:italic>IDH1<\/jats:italic>\n                    mutations are linked to changes in DNA-loop formation leading to oncogene upregulation. Here, we assessed 3D-DNA conformational changes in\n                    <jats:italic>IDH1-<\/jats:italic>\n                    and\n                    <jats:italic>DNMT3A<\/jats:italic>\n                    -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\n                    <jats:italic>IDH1<\/jats:italic>\n                    p.R132H or\n                    <jats:italic>DNMT3A<\/jats:italic>\n                    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\n                    <jats:italic>DNMT3A-<\/jats:italic>\n                    and\n                    <jats:italic>IDH1<\/jats:italic>\n                    -mut AML, which were linked to differential gene expression, supporting that 3D-genome architecture broadly influences transcription. Thereby, loop-mediated upregulation of\n                    <jats:italic>IGF1R<\/jats:italic>\n                    was identified in\n                    <jats:italic>IDH1<\/jats:italic>\n                    -mut AML, corresponding to specific sensitivity to IGF1R inhibitor BMS-754807 as mono- and combination therapy with ivosidenib, while\n                    <jats:italic>DNMT3A<\/jats:italic>\n                    -mut AML exhibited sensitivity to p38\/MAPK inhibitor ralimetinib. Our data present a comprehensive map of global 3D-DNA alterations associated with\n                    <jats:italic>IDH1<\/jats:italic>\n                    - and\n                    <jats:italic>DNMT3A<\/jats:italic>\n                    mutations as a basis for further assessment of novel therapeutic strategies for both AML entities.\n                  <\/jats:p>","DOI":"10.1038\/s41375-026-03152-5","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T11:08:35Z","timestamp":1790852915000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Alterations in 3D-DNA architecture drive unique leukemic profiles in IDH1- and DNMT3A-mutant acute myeloid leukemia"],"prefix":"10.1038","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6985-0896","authenticated-orcid":false,"given":"Sophie","family":"Steinh\u00e4user","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8667-8394","authenticated-orcid":false,"given":"Varun K. 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