Isocitrate dehydrogenase 1 mutations drive downregulation of IL1R1 and dysregulated inflammatory response in acute myeloid leukemia

Sep 30, 2026

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Acute myeloid leukemia (AML) is a genetically heterogeneous hematologic malignancy shaped by both intrinsic mutations and extrinsic inflammatory cues. This correspondence examines how isocitrate dehydrogenase 1 (IDH1) mutations affect IL1R1 signaling and inflammatory programs. Gene-expression analyses across independent AML cohorts show broad downregulation of immune and inflammatory pathways in IDH1-mut AML, aligning with IL1R1-low transcriptional profiles. DNA methylation profiling identifies IL1R locus hypermethylation in IDH1-mut AML, and IL1R1-low patients exhibit higher remission rates and improved survival. Results connect IDH1-mut genotype to IL1R-family downregulation and clinically favorable outcome through reduced IL1R-mediated signaling.

LanguageEnglish

CategoryHealthcare

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Pages5

Reading Time13 min

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Correspondence

Background and rationale

Genotype-specific pathway analysis

IL1R1 expression, methylation, and clinical impact

Blood Cancer [Journal](Journal www.nature.com/bcj)[ www.nature.com/bcj](Journal www.nature.com/bcj) CORRESPONDENCE OPEN Isocitrate dehydrogenase 1 mutations drive downregulation of IL1R1 and dysregulated inﬂammatory response in acute myeloid leukemia © The Author(s) 2026 Blood Cancer Journal (2026)16:5; [https://doi.org/](https://doi.org/)[ ](https://doi.org/)[10.1038/s41408-025-01445-z](10.1038/s41408-025-01445-z) To the editor: Acute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by clonal proliferation and impaired differentiation of myeloid progenitor cells [1]. AML predominantly affects older adults and exhibits substantial genetic heterogeneity, including structural chromosomal alterations and recurrent somatic mutations [2] . In the 2022 WHO/ICC classiﬁcations, AML entities are deﬁned by recurrent genetic alterations [3, 4]. Among these, mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 occur in approximately 10–20% of cases and deﬁne a metabolically and epigenetically distinct subgroup [5]. The IDH1 p.R132H mutation produces the oncometabolite 2-hydroxyglutarate, which inhibits α-KG-dependent dioxygenases such as TET enzymes and induces DNA hypermethylation and transcriptional repression, thereby blocking hematopoietic differentiation and promoting leukemogenesis [6] . In addition to cell-intrinsic mutations, AML progression is inﬂuenced by extrinsic factors. Among these, the bone marrow niche contributes to a permissive and pro-inﬂammatory microenvironment that fosters leukemic proliferation and suppresses normal hematopoiesis [7] . A key mediator of this inﬂammatory milieu is IL-1/IL1R1 signaling, which disrupts hematopoietic stem-cell function and promotes early leukemic expansion [8, 9] . While the metabolic and epigenetic consequences of IDH1 mutations are well deﬁned, it remains unclear whether IDH1-mutant (mut) AML (i) drives distinct intracellular signaling programs and (ii) shows an altered sensitivity to pro-inﬂammatory conditions in the bone marrow niche, thereby inﬂuencing treatment response and disease progression. These ﬁndings raise the question of how genetically deﬁned AML subtypes - such as IDH1-mut AML - are shaped by inﬂammatory signals in the bone marrow niche. To identify genotype-speciﬁc signaling pathways of IDH1-mut AML, we analyzed gene expression proﬁles from two independent AML cohorts (BeatAML2.0 and GSE146173; Fig. 1A, S1). Based on differential gene expression analysis (Table S2), gene set enrichment analysis (GSEA) identiﬁed pathway-level alterations between IDH1-mut and IDH1-wt AML samples. Among 39 signiﬁcantly enriched pathways, 32 (82%) were downregulated in IDH1-mut AML, with 22 (69%) related to immune or inﬂammatory signaling (Fig. S2A). The top three downregulated hallmark pathways inﬂammatory response, IL6/JAK/STAT3 signaling and interferongamma response - were consistently reduced in both cohorts (Fig. S2B/C). Similarly, in IL1R1-low AML cases, a suppression of inﬂammatory Hallmark and KEGG pathways was observed compared to IL1R1-high AML (Fig. S3, Table S3), mirroring the transcriptional proﬁle of IDH1-mut AML. Based on the GSEA results from the IDH1-mut vs. IDH1-wt comparison, integration of the top three hallmark pathways with downregulated genes from the BeatAML2.0 dataset identiﬁed 43 overlapping candidates (Fig. S4, Table S4) . Protein-protein interaction network analysis (STRING) revealed four functional clusters, including one centered on IL1R1 and related genes (IL1R2, IL18R1, IL18RAP), highlighting dysregulation of IL1R-family signaling, alongside modules linked to pattern recognition, TNF signaling and interferon responses (Fig. 1B). Comparison across genotypes conﬁrmed that IL1R-family genes were speciﬁcally downregulated in IDH1-mut AML, but not in IDH2-mut cases (Figs. 1C, S5A). In contrast, genes associated with TNF signaling, pattern recognition and interferon-stimulated pathways were reduced in both IDH1-and I

FAQs

Why are IDH1 mutations studied in acute myeloid leukemia?

IDH1 mutations define a metabolically and epigenetically distinct AML subgroup and may reshape how inflammatory cues in the bone marrow niche influence disease progression and treatment response.

What do the pathway analyses show for IDH1-mut AML?

Differential expression and GSEA reveal that many immune/inflammatory pathways are significantly downregulated in IDH1-mut AML, including key inflammatory response programs.

How is IL1R1 linked to patient outcomes in AML?

Patients with low IL1R1 expression have higher complete remission rates and longer overall survival, and IL1R1 remains independently associated with favorable outcome in multivariable models.

Sep 30, 2026

Uploaded by Asher