Abstract
Abstract
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.