Inflammatory signatures in the spectrum of myeloid diseases

Abstract Dysregulated innate immunity contributes to clonal cytopenias and myeloid neoplasms, but its extent across disease stages and clinical relevance remain incompletely defined. We analyzed plasma ASC/NLRP3 double‐positive (DP) specks, ASC single‐positive (SP) specks, and 45 cytokines in 223 patients with idiopathic cytopenias of undetermined significance (ICUS)/clonal cytopenias of undetermined significance (CCUS), myelodysplastic syndromes (MDS), and chronic myelomonocytic leukemia (CMML) and 39 matched non‐inflammatory controls using adjusted regression, survival modeling, and paired longitudinal analyses. Inflammasome activation and cytokine perturbations were evident across the disease spectrum. DP‐ASC specks were elevated in MDS and CMML, whereas SP‐ASC specks were increased across all groups, indicating activation of ASC‐containing inflammasomes beyond NLRP3. Cytokines followed a graded ICUS → MDS → CMML pattern, with widespread upregulation of interleukins and chemokines (including IL‐7, IL‐8, IL‐11/CXCL11, and CCL7) alongside suppression of stem and progenitor support factors such as CSF3, FLT3LG, TRAIL, and TWEAK. At baseline, elevated IL‐15 and MMP1 predicted progression to acute myeloid Leukaemia, while higher IL‐10, CXCL8, and IL‐18 were associated with reduced survival; ASC specks were not independently prognostic. Longitudinal increases in selected cytokines distinguished progressors (area under the curve 0.82; 95% CI: 0.49–1.0). Cytokine patterns correlated with mutation categories, with the isolated SF3B1 mutation associated with higher DP‐ASC specks. These findings define early and progressive inflammasome engagement and nominate dynamic cytokine panels and the inflammasome–IL‐1 axis as actionable biomarkers and therapeutic targets.