Title: DNMT3A Co-mutation and Immune Exclusion Signatures Define Outcomes in AML with IDH2 Mutations

Background

Isocitrate dehydrogenase 2 (IDH2)–mutated acute myeloid leukemia (AML) exhibits distinct co-mutation patterns as well as metabolic and epigenetic features. Although mutant IDH–derived oncometabolites may impair antitumor immunity, the transcriptomic basis of immune dysfunction and its prognostic relevance in IDH2-mutated (IDH2^mut) AML remain incompletely understood.

Objective/Aim

We integrated genomic and transcriptomic profiling to dissect the heterogeneity of IDH2^mut AML.

 

Methods

We analyzed 1,039 de novo non-M3 AML patients treated with standard chemotherapy, with targeted mutational profiling and bulk RNA-seq analysis.  Single-cell RNA sequencing (scRNA-seq) (GSE116256) were used to delineate the cell-type specific dysregulations.

 

Results

IDH2 mutations were identified in 11.9% of patients (R140 7.9%, R172 3.0%). Concurrent DNMT3A mutations were associated with worse OS (P=0.007) and EFS (P=0.038) in those with IDH2 R140 but not those with R172 mutations, which were validated in AMLSG cohort.

Compared to IDH2^wt AML, IDH2^mut AML displayed significant negative enrichment of interferon-α (IFN-α) (NES -1.76, FDR 2.25E-3), IFN-γ signaling (NES -2.07, FDR 2.65E-8), and allograft rejection signatures (NES -2.31, FDR 2.50E-9), consistent with an immune exclusion phenotype. IDH2^mut patients with short EFS (<2 years) showed stronger immune exclusion, with CXCL10, KLF1, and CTSL identified as key DEGs that also stratified OS in BEAT-AML cohort. In scRNA-seq analyses, a total of 10722 cells derived from 9 IDH2wt and 2 IDH2mut patients were analyzed. IFN-α pathway module scores were higher in monocytes, and T cells than progenitor cells. IDH2^mut AML exhibited reduced IFN-α module scores specifically within progenitor cells.

 

Conclusions 

In conclusion, DNMT3A co-mutation confers adverse prognosis in IDH2 R140 AML. IDH2 mutations are associated with immune exclusion, particularly in progenitor cells, highlighting the relevance of host immunity in shaping prognosis.