S100A9 alarmin signaling
Current understanding
S100A9 is a calcium-binding alarmin/damage-associated molecular pattern protein released by myeloid cells that drives chronic innate-immune inflammation, myeloid-derived suppressor cell activity, and HDAC4-mediated transcriptional programs implicated in fibrotic and myeloproliferative disease. In myelofibrosis, S100A9 is hypothesized to sustain the inflammatory bone marrow milieu and clonal advantage downstream of and parallel to JAK-STAT signaling. Tasquinimod, a first-in-class S100A9/HDAC4 inhibitor, is now being clinically tested (alone and with ruxolitinib) as the first therapeutic probe of this axis in MPN.
Evidence log
- 2026-08-03 — Spatially resolved transcriptomic profiling of myelofibrosis spleen reveals compartment specific niche programs.: Spatial transcriptomics localizes S100A8/A9 alarmin expression specifically to the red-pulp EMH compartment of MF spleen, providing anatomic grounding for the alarmin axis as a spatially restricted feature of extramedullary myelopoiesis rather than a diffuse splenic program. (novelty: 4)
- 2026-08-03 — Non-invasive multiparametric characterization of essential thrombocythemia, premyelofibrosis, and overt myelofibrosis.: Non-invasive multiparametric profiling across ET, preMF, and PMF includes matrix-regulator and alarmin-associated markers as part of the panel that discriminates fibrotic MPN subtypes, offering circulating-biomarker support for S100A9-family/DAMP involvement along the ET→PMF continuum. (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): cross-connection with inflammatory-cytokine-signaling: S100A9 acts as an alarmin upstream of and parallel to canonical IL-6/TNF cytokine cascades, providing a mechanistic link between innate-immune DAMP signaling and the broader inflammatory cytokine milieu in MPN. (novelty: 4)
Open questions
Related
Contributing findings
Spatially resolved transcriptomic profiling of myelofibrosis spleen reveals compartment specific niche programs.
03-aug-2026
novelty 4
per-area 3
strengthens
Non-invasive multiparametric characterization of essential thrombocythemia, premyelofibrosis, and overt myelofibrosis.
03-aug-2026
novelty 3
per-area 3
strengthens
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
13-apr-2026
novelty 3
per-area 2
mentions
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)
27-feb-2026
novelty 4
per-area 4
introduces