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Publications

Journal Article Epublish

PubMed: 42620871 DOI: 10.1177/20406207261474950

Immune and cytokine landscape differs between cytopenic and proliferative phenotypes in primary myelofibrosis.

Ther Adv Hematol 17:20406207261474950

Authors: Sze-Hwei Lee, Yu-Hung Wang, Yu-Sung Chang, Chao-Hung Wei, Chang-Tsu Yuan, Hsin-An Hou, Wen-Chien Chou, Hwei-Fang Tien, Chien-Chin Lin

Affiliations

  • Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, Taiwan. Division of Cellular Therapy, Department of Integrated Diagnostics and Therapeutics, National Taiwan University Hospital, Taipei, Taiwan.
  • Department of Hematological Oncology, National Taiwan University Cancer Center, Taipei, Taiwan.
  • Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
  • Department of Pathology, National Taiwan University Cancer Center, Taipei, Taiwan.
  • Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan.

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 fewer JAK2 mutations (P=0.025) but were enriched for high molecular risk mutations such as ASXL1 (P=0.011) and EZH2 (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.

MeSH

Cytokines, Fibrosis, Phenotype, Mutation, Primary Myelofibrosis, Cytopenia