Transcriptomic and epigenetic changes contribute to the development of splenic extramedullary hematopoiesis in myelofibrosis [scATAC-seq]

To explore the molecular mechanisms underlying splenic EMH, we performed single cell transcriptional and chromatin profiling of cells from MF spleens that had been surgically removed. We demonstrate significant expansion of hematopoietic stem and progenitor cells coupled to aberrant differentiation towards the erythroid and megakaryocytic lineages associated with a significant enrichment of inflammatory pathways with enhanced NF-kB signaling and IFN responses as well as dysregulation of the inferred function of differentiation-defining transcription factors.

Finally, we report a significant remodeling of the immune microenvironment in MF spleens, characterized by emergence of dysfunctional T cell subsets and inflammatory memory B cells suggesting the concomitant establishment of a pro-inflammatory and immune-tolerant tumor microenvironment within the spleen that influences hematopoietic cell differentiation and impairs tumor immune surveillance.