Immunomodulatory role of megakaryocytes in the hematopoietic niche of myeloproliferative neoplasms

Abstract

Myeloproliferative neoplasms (MPNs) are clonal stem cell disorders characterized by dysregulated megakaryopoiesis and expansion of neoplastic hematopoietic stem cells (HSCs). Megakaryocytes (MKs) not only regulate HSC function but also shape immune responses within the marrow niche. Using an aging murine model of MPN with MK-restricted JAK2V617F expression, we investigated the immunomodulatory roles of mutant MKs. Compared to wild-type MKs, aged mutant MKs exhibit enhanced antigen uptake and MHC I presentation, secretion of pro-inflammatory cytokines (PF4, TGFβ, IL-1β), and induction of T cell dysregulation in the marrow niche. In chimeric murine models with co-existing wild-type and JAK2V617F mutant hematopoietic cells, enhanced MK immune activity correlates with mutant cell expansion and MPN development. Single-cell RNA sequencing revealed that aging amplifies JAK2V617F MK–driven immune remodeling. Notably, aged mutant MKs showed marked upregulation of LINE-1 (long-interspersed element-1) retrotransposon transcripts alongside elevated innate immune sensors cyclic GMP–AMP synthase (cGAS) and stimulator of interferon genes (STING), implicating retrotransposon activity in niche inflammation. In human MPN marrow, immunohistochemistry detected LINE-1–encoded protein ORF1p in MKs from 12 of 13 MPN patients, but not in orthopedic controls (n=5). These findings identify MKs as active immune regulators in MPNs, with JAK2V617F mutation and aging synergizing to reprogram MKs into inflammatory, immunemodulatory niche cells. LINE-1 activation emerges as a potential driver of chronic marrow inflammation and a targetable mechanism in clonal hematopoiesis and MPN progression.