Inflammatory Network Architecture Across Bone Marrow Failure: An Immune-Genetic Continuum.
Key claim: Inflammatory signaling centered on a TNF-α/IFN-γ/IL-6 module with JAK-STAT and NF-κB hubs is a conserved, context-dependent modifier across bone marrow failure syndromes including MPNs and myelofibrosis, with TGF-β linking inflammation to fibrotic remodeling and germline versus somatic genetics biasing attrition versus clonal expansion.
Abstract
Bone marrow failure (BMF) syndromes encompass inherited disorders, immune-mediated aplasia, and clonal myeloid neoplasms, which share overlapping biology but divergent clinical trajectories. Inflammation shapes hematopoietic stem and progenitor cell fate across this spectrum, yet its network organization, genetic conditioning, and therapeutic implications remain incompletely defined. An integrative, literature-based analysis of inflammatory cytokines, genetic contexts, and therapeutic targeting across major BMF disorders, including inherited BMF syndromes, aplastic anemia (AA), myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), and myelofibrosis (MF). Gene-inflammation-outcome networks and co-occurrence maps were constructed with stratification by germline and somatic alterations. Therapeutic activity was mapped across cytokine-directed and pathway-targeted agents. Inflammatory signaling emerged as a conserved feature across all BMF categories, with TNF-α, IFN-γ, and IL-6 forming a recurrent core module, and TGF-β linking inflammatory programs to fibrotic remodeling.- and-associated pathways appeared as central nodes integrating multi-cytokine inputs. Germline lesions in, andwere predominantly associated with apoptotic stem-cell attrition. In contrast, somatic drivers, including, and, were more frequently associated with clonal expansion. Multi-cytokine convergence on shared effectors was common, suggesting pathway redundancy. The therapeutic literature predominantly focused on TNF-α/IFN-γ/IL-6 pathways, with comparatively limited exploration of TGF-β, IL-8, and IL-17. These findings support a role for inflammation as a unifying, context-dependent modifier across the BMF spectrum, and highlight- and-centered circuitry as potential nodes for rational combination strategies. TGF-β, IL-8, and IL-17 axes and inherited BMF entities represent underexplored opportunities for biomarker-guided cytokine-directed intervention.
Why this matters
Placing MPNs and myelofibrosis on a shared BMF inflammatory-network continuum reframes subtype-specific natural history — PMF’s fibrotic drift, MDS/MPN overlap’s dysplastic-proliferative mixing, and MPN clonal expansion generally — as different outputs of the same TNF-α/IFN-γ/IL-6 → JAK-STAT/NF-κB → TGF-β circuitry conditioned by germline versus somatic genetics. That framing rationalizes the convergence of JAKi, IL-1β (canakinumab), CSF-1R (axatilimab), TGF-β trap (elritercept, luspatercept), and BET-inhibitor programs across these subtypes and predicts that inflammatory-modifier response will vary by genetic context rather than by histologic label alone.