Spatially resolved transcriptomic profiling of myelofibrosis spleen reveals compartment specific niche programs.
Key claim: Spatial transcriptomics of myelofibrosis spleen reveals three compartment-specific niche programs—intravascular endothelial/vascular-stress, perivascular fibro-remodeling with CXCL12 retention cues, and red-pulp EMH with S100A8/A9 alarmins—supporting a division of labor underlying splenomegaly.
Abstract
Myelofibrosis (MF) splenomegaly reflects not only extramedullary hematopoiesis (EMH) but a compartmental organization of the splenic microenvironment into spatially distinct niches. Using Spatial whole transcriptome profiling on FFPE spleen tissue from three MF patients, we interrogated three anatomically defined compartments: Intravascular (IV), Perivascular (PV) and Red Pulp (RP). Differential expression was estimated through pairwise compartment contrasts with Benjamini-Hochberg false discovery rate correction (FDR < 0.05, |log2FC|≥1), and compartment “core signatures” were defined by directional concordance across the two contrasts relevant to each compartment. IV regions of interest (ROIs) showed an endothelial/adhesion and vascular stress program (e.g., PECAM1, VCAM1; antioxidant enzymes). PV ROIs were characterized by fibro-remodeling and immune-structured signals (COL1A1/COL3A1, LOXL1, MMP2/TIMP1; HLA‑DRA/CD74) including CXCL12, consistent with a PV niche coupling extracellular matrix remodeling to hematopoietic retention cues. RP ROIs captured an EMH-associated erythroid/heme program (ALAS2, FECH, BLVRB) with stress and inflammatory alarmins (S100A8/S100A9). Together, these findings support a compartmental “division of labor” in MF spleen, vascular interface activation, PV remodeling/chemokine niches, and RP EMH/redox stress, providing a spatial framework to interpret splenomegaly as structured niche dependencies and to prioritize candidate microenvironmental dependencies for follow‑up validation.
Why this matters
Splenomegaly in myelofibrosis is the dominant driver of mechanical symptoms (early satiety, pain, cytopenias) and is currently managed with bulk-reduction strategies (JAK inhibitors, radiation, splenectomy). Resolving the spleen into three spatially distinct niche programs suggests future symptom-directed therapies could target the specific compartment driving a given patient’s burden — e.g., CXCL12 axis for perivascular retention or S100 alarmins for red-pulp inflammatory EMH — rather than relying on global cytoreduction alone.