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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.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/isocitrate-dehydrogenase-1-mutations-drive-downregulation-of-il1r1-and-dysregulated-inflammatory-response-in-acute-myeloid-leukemia/453455/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/isocitrate-dehydrogenase-1-mutations-drive-downregulation-of-il1r1-and-dysregulated-inflammatory-response-in-acute-myeloid-leukemia/453455.png","ImageObject",300,407,{"name":92,"@type":93},"Asher","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-02","2026-09-30",true,{"@type":102,"interactionType":103,"userInteractionCount":44},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why are IDH1 mutations studied in acute myeloid leukemia?","Question",{"text":112,"@type":113},"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.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What do the pathway analyses show for IDH1-mut AML?",{"text":117,"@type":113},"Differential expression and GSEA reveal that many immune/inflammatory pathways are significantly downregulated in IDH1-mut AML, including key inflammatory response programs.",{"name":119,"@type":110,"acceptedAnswer":120},"How is IL1R1 linked to patient outcomes in AML?",{"text":121,"@type":113},"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.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},453455,1791283921,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":44,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":24,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":144,"preview_page_count":4},687197207639,"https://ap-avatar.wpscdn.com/davatar_a8503ba1806abce46bf441b54a3ca4cd","Blood Cancer [Journal](Journal www.nature.com/bcj)[ www.nature.com/bcj](Journal www.nature.com/bcj)  \nCORRESPONDENCE OPEN   \nIsocitrate dehydrogenase 1 mutations drive downregulation of IL1R1 and dysregulated inflammatory response in acute myeloid leukemia  \n© The Author(s) 2026  \nBlood 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)  \nTo the editor:  \nAcute 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.  \nTo 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  \ncompared 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","cbCaihcli843qD0X","https://ap.wps.com/l/cbCaihcli843qD0X","pdf",1753419,"English","# Correspondence\n## Background and rationale\n## Genotype-specific pathway analysis\n## IL1R1 expression, methylation, and clinical impact","[{\"question\":\"Why are IDH1 mutations studied in acute myeloid leukemia?\",\"answer\":\"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.\"},{\"question\":\"What do the pathway analyses show for IDH1-mut AML?\",\"answer\":\"Differential expression and GSEA reveal that many immune/inflammatory pathways are significantly downregulated in IDH1-mut AML, including key inflammatory response programs.\"},{\"question\":\"How is IL1R1 linked to patient outcomes in AML?\",\"answer\":\"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.\"}]","Isocitrate dehydrogenase 1 mutations drive downregulation of IL1R1 and dysregulated inflammatory response in acute myeloid leukemia | PDF",1790738905,13]