Inflammatory cytokine signaling

Current understanding

Elevated IL-6, IL-8, TNF-alpha, and other cytokines drive MPN constitutional symptoms (fatigue, pruritus, weight loss) and contribute to clonal advantage.

Evidence log

• 2026-09-16 — Canakinumab or emavusertib for anemia in lower-risk MDS: results of the CANFIRE and LUCAS phase 2, open-label, multicenter trials.: Two early-terminated phase-2 trials (CANFIRE canakinumab; LUCAS emavusertib) showed neither IL-1β nor IRAK4 blockade produced erythroid hematologic improvement in lower-risk MDS or MDS/MPN, weakening the therapeutic tractability of the IL-1β→IRAK4→NF-κB cytokine axis for anemia rescue at this disease stage. (novelty: 3)
• 2026-09-15 — Type 1 interferon perturbates clonal competition by reshaping human blood development.: Type I IFN signaling is shown to bifurcate human HSC differentiation into anti-inflammatory lymphoid vs inflammatory myeloid states, framing IFNα not as a uniform inflammatory driver but as a polarizing signal whose myeloid arm mutant HSCs evade. (novelty: 4)
• 2026-07-09 — Glutamate accumulation in myelofibrosis microenvironment rewires mesenchymal stromal cells metabolic and epigenetic profiles.: Preclinical evidence positions extracellular glutamate as a non-cytokine microenvironmental signal that reprograms MSCs via mGluR5, adding a neurotransmitter-receptor axis to the MF inflammatory/microenvironmental milieu. (novelty: 5)
• 2026-08-03 — Spatially resolved transcriptomic profiling of myelofibrosis spleen reveals compartment specific niche programs.: Spatial profiling of MF spleen partitions the inflammatory milieu into compartment-specific programs — vascular-stress endothelial signatures intravascularly, CXCL12-retention fibro-remodeling perivascularly, and S100A8/A9 alarmin output in red-pulp EMH — arguing the splenic cytokine/chemokine landscape is spatially structured rather than uniform. (novelty: 4)
• 2026-08-06 — Collagen Turnover Is Associated with Disease Severity, Bone Marrow Fibrosis, and theVariant Allele Frequency in Myeloproliferative Neoplasms.: Elevated PRO-C3 in MPN tracks with LDH and disease severity, positioning collagen-turnover neoepitopes as a circulating readout downstream of the inflammatory/fibrogenic milieu. (novelty: 3)
• 2026-09-01 — Type-I interferon-activated NK cells control polycythemia vera in vivo.: Preclinical PV models show NK-cell-derived TNF-α is the effector cytokine mediating preferential killing of JAK2V617F-mutant HSPCs under type-I IFN activation, recasting TNF-α from a generic inflammatory driver into a targeted anti-clonal effector when delivered by IFN-primed NK cells. (novelty: 5)
• 2026-06-26 — Increased Mast Cell Numbers in Bone Marrow of Patients with Myeloproliferative Neoplasms and Pruritus.: Observational MPN cohort links pruritus symptom burden to elevated bone-marrow mast-cell counts, implicating mast-cell-derived mediators as a candidate effector arm of the MPN inflammatory milieu underlying pruritus alongside IL-6/IL-8/TNF cytokine drivers. (novelty: 3)
• 2026-07-14 — Targeting nuclear export and Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signalling in myelofibrosis: A novel combinatorial strategy that impacts intrinsic and microenvironment-related pathways.: Preclinical study shows selinexor + ruxolitinib disrupts NF-κB-driven inflammatory cytokine output in both malignant MF cells and stromal/microenvironment compartments, linking XPO1 nuclear export to NF-κB inflammatory programs beyond JAK-STAT. (novelty: 3)
• 2026-08-03 — Non-invasive multiparametric characterization of essential thrombocythemia, premyelofibrosis, and overt myelofibrosis.: Prospective multiparametric profiling shows circulating inflammatory and immune-activation markers discriminate overt PMF and partially separate prefibrotic MF from ET, supporting an inflammatory cytokine continuum tracking with fibrotic progression across MPN subtypes. (novelty: 3)
• 2026-08-18 — Immune and cytokine landscape differs between cytopenic and proliferative phenotypes in primary myelofibrosis.: Multi-modal profiling (transcriptomic, cytokine, IHC) in PMF identifies NF-κB activation with elevated IL-8 and G-CSF as the inflammatory signature specifically distinguishing cytopenic from proliferative PMF, refining the MPN inflammatory milieu into phenotype-linked subprograms rather than a uniform cytokine burden. (novelty: 3)
• 2026-08-25 — Spatial profiling of the spleen in mouse and human myelofibrosis reveals complement-driven immune-stromal interactions as a therapeutic target.: Spatial profiling implicates complement C3 as an under-recognized arm of the MPN inflammatory milieu, driving inflammatory reprogramming of splenic stromal cells that support extramedullary hematopoiesis and fibrosis (preclinical). (novelty: 5)
• 2026-08-01 — Inflammatory Network Architecture Across Bone Marrow Failure: An Immune-Genetic Continuum.: Cross-BMF review frames a conserved TNF-α/IFN-γ/IL-6 inflammatory core with JAK-STAT and NF-κB as central hubs, positioning MPN/MF inflammatory signaling as one instance of a shared architecture spanning bone marrow failure syndromes. (novelty: 3)
• 2026-09-03 — Targeting Thrombopoietin/MPL Signaling to Mitigate JAK2V617F-Driven Cardiac Microvascular Disease.: Preclinical evidence implicates endocardial thrombopoietin/MPL signaling — induced by JAK2V617F-mutant blood cells under cardiometabolic stress — as a mediator of cardiac microvascular injury, adding a TPO/MPL axis to the MPN-driven cardiovascular inflammatory milieu. (novelty: 4)
• 2026-04-27 — JAK Inhibitor-Induced Improvement of IgA Nephropathy in a Patient With Polycythemia Vera: A Case Report.: Case report proposes IL-6 and IL-11 as JAK-STAT-driven mediators of mesangial proliferation in MPN-associated IgA nephropathy, adding a glomerular end-organ manifestation to the MPN inflammatory cytokine milieu. (novelty: 4)
• 2026-06-23 — Galectin-1 Fuels Monocyte Hyperinflammation and Represents a Novel Therapeutic Target in Myeloproliferative Neoplasms.: Galectin-1 (LGALS1) identified as a novel monocyte-intrinsic amplifier of the MPN inflammatory cytokine program through TLR4–NF-κB engagement, expanding the upstream drivers of NF-κB-mediated cytokine output beyond IL-1β/IRAK1/S100A9 axes. (novelty: 5)
• 2025-10-30 — Effective Treatment with Ruxolitinib and Ropeginterferon Alfa-2b for Refractory TAFRO-like Syndrome.: Refractory TAFRO-like syndrome (a hypercytokinemic state) in a JAK2 V617F PV patient resolved with ruxolitinib + ropeginterferon alfa-2b, implicating JAK-STAT-driven inflammatory cytokine output as the mechanistic substrate of this rare MPN-associated hyperinflammatory complication. (novelty: 3)
• 2026-06-16 — Lysozyme-Associated Nephropathy in Myeloid Neoplasms: A Clinicopathological and Mass Spectrometric Study of Two Cases.: Case report of lysozyme-associated nephropathy in PMF and CMML links sustained monocyte/granulocyte-derived lysozyme overproduction (a downstream output of the MPN inflammatory/myelomonocytic milieu) to end-organ proximal tubular injury, extending the systemic consequences of MPN-driven myelomonocytic inflammation to the kidney. (novelty: 4)
• 2026-03-20 — Association between JAK2 Mutations and Thoracic Aortic Aneurysms in Myeloproliferative Neoplasms: Scoping review of JAK2-MPN and thoracic aortic aneurysm implicates chronic JAK-STAT-driven inflammatory cytokine signaling as a candidate mediator of aortic wall degeneration, paralleling CHIP-associated inflammaging mechanisms of aneurysm formation. (novelty: 4)
• 2026-06-05 — The impact of novel bet inhibitors on the treatment armamentarium of Myelofibrosis.: Review positions BET bromodomain inhibition (pelabresib) as a transcription-level brake on NF-κB-driven inflammatory cytokine output in MF, mechanistically distinct from direct IL-1β, IRAK1, or S100A9 blockade but converging on the same inflammatory milieu. (novelty: 3)
• 2026-05-10 — Scalable genotyping in fixed transcriptomes resolves clonal heterogeneity via single-cell sequencing: GIFT single-cell data identify an interferon-associated transcriptional gradient in JAK2V617F-mutant HSCs proportional to allele dose, implicating IFN-pathway signaling as a cell-intrinsic, dosage-tuned component of the MPN inflammatory milieu distinct from secreted IL-6/IL-1β/TNF programs. (novelty: 5)
• 2026-04-13 — A Phase II, Open-Label, Study of Subcutaneous Canakinumab, an Anti-IL-1β Human Monoclonal Antibody, for Patients With Low or Int-1 Risk IPSS/IPSS-R Myelodysplastic Syndromes and Chronic Myelomonocytic Leukemia: Phase II trial of subcutaneous canakinumab (anti-IL-1β mAb) in low/Int-1 risk MDS and CMML extends IL-1β-directed therapy beyond MF into earlier-stage myeloid neoplasms, reinforcing IL-1β as a shared inflammatory driver across the MDS/MPN spectrum. (novelty: 3)
• 2026-03-13 — Axatilimab With or Without Azacitidine for the Treatment of Patients With Advanced Phase Myeloproliferative Neoplasms, Myeloproliferative Neoplasm/Myelodysplastic Syndrome Overlap or High Risk Chronic Myelomonocytic Leukemia: Phase Ib/II trial of axatilimab (anti-CSF-1R mAb) ± azacitidine in advanced MPN, MPN/MDS overlap, and high-risk CMML tests whether depleting/inhibiting CSF-1R-dependent macrophages can attenuate the inflammatory cytokine milieu, adding a macrophage-targeted arm distinct from IL-1β, S100A9, IRAK1/NF-κB, and JAK-STAT strategies. (novelty: 4)
• 2026-02-18 — A New Diagnostic Algorithm to Non-invasively Track Fibrotic Changes in Myeloproliferative Neoplasms Based on C-C Chemokine Receptor 2 Detection. From Flow Cytometry to the Development of Targeted Positron Emission Tomography Molecular Imaging. Pre-clinical Studies and First In-human Proof of Concept: CCR2 (the receptor for CCL2/MCP-1) is identified on circulating and marrow-resident cells in MPN patients with fibrotic progression, extending the inflammatory cytokine/chemokine axis to include CCL2-CCR2-mediated monocyte recruitment as a candidate driver of fibrosis. (novelty: 4)
• 2026-02-06 — Pacritinib For Bone Marrow Fibrosis In Patients With Myelofibrosis Who Have Thrombocytopenia: PACRIMYEL phase II trial of pacritinib in thrombocytopenic MF tests whether IRAK1-mediated NF-κB blockade (alongside JAK2 inhibition) can suppress the inflammatory/fibrotic cytokine program, positioning IRAK1/NF-κB as a clinically tractable arm of MPN inflammatory signaling distinct from IL-1β-, S100A9-, or JAK-STAT-directed strategies. (novelty: 4) (novelty: 4)
• 2026-03-27 — Curcumin to Improve Inflammation and Symptoms in Patients With Clonal Cytopenia of Undetermined Significance, Low Risk Myelodysplastic Syndrome, and Myeloproliferative Neoplasms: Phase II trial evaluates curcumin (C3 complex/Bioperine) supplementation in CCUS, LR-MDS, and MPN patients to reduce inflammatory cytokine burden and symptom severity, testing a nutraceutical anti-inflammatory strategy distinct from targeted cytokine blockade. (novelty: 3)
• 2026-03-19 — Study of Canakinumab in Patients With Myelofibrosis: Phase 2 trial of canakinumab (anti-IL-1β monoclonal antibody) in PMF and post-ET/PV MF tests direct IL-1β neutralization as a therapeutic strategy, implicating IL-1β specifically (beyond IL-6/TNF/IL-8) as a tractable driver of MF pathobiology. (novelty: 4)
• 2026-03-06 — Identification of Factors Associated With Treatment Response in Patients With Polycythemia Vera, Essential Thrombocythemia, and Pre-myelofibrosis.: Protocol study proposes baseline cytokine profile at diagnosis as a candidate predictor of 12-month hematological response to hydroxyurea or pegylated interferon in PV, ET, and pre-MF, framing the inflammatory milieu as a treatment-response biomarker rather than only a symptom driver. (novelty: 3)
• 2026-02-27 — Open Label Phase 1/2 Study of Tasquinimod in Patients With Primary Myelofibrosis (PMF), Post-Polycythemia Vera Myelofibrosis (Post-PV MF), or Post-Essential Thrombocytosis Myelofibrosis (Post-ET MF): Phase 1/2 trial of tasquinimod (S100A9/HDAC4 inhibitor) ± ruxolitinib in PMF/post-PV/post-ET MF introduces pharmacologic targeting of the S100A9 alarmin axis as a novel anti-inflammatory strategy distinct from cytokine-receptor or JAK-STAT blockade. (novelty: 4)
• 2026-01-06 — Key Oncology Drugs Granted FDA Designations in January 2026: 2026-01 — FDA orphan drug designation for CK0804, an allogeneic regulatory T-cell (Treg) therapy reporting reductions in spleen volume, symptom burden, and transfusion burden in heavily pretreated MF, indirectly supporting a role for immune/Treg-mediated modulation of the inflammatory milieu in myelofibrosis. (novelty: 4, evidence: regulatory/other) (novelty: 4)

Open questions

Related mechanisms

• jak-stat-signaling
• thrombosis-risk