Immune and cytokine landscape differs between cytopenic and proliferative phenotypes in primary myelofibrosis.
Key claim: Cytopenic primary myelofibrosis is a biologically distinct, clinically aggressive phenotype characterized by NF-κB inflammatory pathway activation, elevated IL-8 and G-CSF, and enrichment for high-molecular-risk mutations versus proliferative PMF.
Abstract
BACKGROUND: Cytopenia represents a distinct clinical phenotype in primary myelofibrosis (PMF), often associated with advanced disease and poor prognosis. We propose that while a common driver mutation initiates the disease, the clinical phenotype of PMF is shaped by inter-individual variability in downstream inflammatory responses, contributing to the observed heterogeneity in disease presentation. OBJECTIVES: To characterize inflammatory and immune signatures distinguishing cytopenic from proliferative phenotypes of PMF. DESIGN: Retrospective, single-center observational study analyzing clinical, molecular, transcriptomic, and cytokine data from patients with pathologically confirmed PMF. METHODS: We analyzed a cohort of 140 patients with PMF, stratified into cytopenic and proliferative phenotypes based on abnormalities in at least one peripheral blood lineage. Bone marrow transcriptomic profiling was performed using the NanoString nCounter PanCancer Immune Panel. Cytokine levels were measured by MILLIPLEX® bead-based multiplex assay, and phosphorylated NFκB p65 expression was evaluated by immunohistochemistry. RESULTS: Compared with the proliferative phenotype, cytopenic PMF showed more advanced disease features, including higher blast counts (P<0.001), elevated LDH (P<0.001), and more frequent overt fibrosis (P<0.001). Cytopenic patients had fewermutations (P=0.025) but were enriched for high molecular risk mutations such as(P=0.011) and(P=0.035). Transcriptomic profiling revealed upregulation of inflammatory pathways, notably TNFα-NFκB (P=0.0097) and IL2-STAT5 (P=0.0399), while cytokine analysis showed elevated IL-8 (P=0.021) and G-CSF (P=0.007) independent of fibrosis severity. Immunohistochemistry confirmed enhanced NFκB p65 activation in cytopenic marrow. CONCLUSION: Our findings highlight cytopenic PMF as a biologically distinct and clinically aggressive phenotype characterized by inflammatory pathway activation, particularly involving NFκB signaling and elevated IL-8. These results support the role of immune dysregulation in the pathogenesis of cytopenia in PMF and provide a basis for further investigation into its clinical implications.
Why this matters
Cytopenic and proliferative PMF are increasingly treated as distinct clinical entities (driving JAKi selection between ruxolitinib, pacritinib, and momelotinib), but the biological basis has been underspecified. This study provides multi-modal evidence that cytopenic PMF is inflammatorily distinct — NF-κB activation with IL-8/G-CSF elevation and HMR mutation enrichment — reinforcing why cytopenic disease behaves more aggressively and rationalizing the NF-κB/IRAK1-targeting (pacritinib) and inflammation-directed (canakinumab, tasquinimod, BET inhibitors) strategies concentrated in this subpopulation.