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

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.