HiJAKing the hematopoietic system: a low-frequency JAK2V617F clone drives myeloproliferative neoplasm pathology

Abstract JAK2V617F is one of the most common mutations in clonal hematopoiesis of indeterminate potential (CHIP) and a major driver of myeloproliferative neoplasms (MPNs). To determine the impact of a low-frequency JAK2V617F clone on both the hematopoietic system and the bone marrow (BM) stroma, we developed a traceable murine MPN model, in which whole BM transplantation (BMT) was performed using CD45.2 5.0 × 106 JAK2V617F donor cells transplanted into unconditioned CD45.1 recipient mice. BMT recipients developed a polycythemia vera–like phenotype (elevated hematocrit and leukocytosis) with a 2.7% average donor cell chimerism in peripheral blood. Eight months after BMT, RNA sequencing (RNA-seq) analysis of BM cells sorted according to CD45.1/CD45.2 expression showed significant upregulation of early erythroblast- and myeloid cell–specific transcripts, and downregulation of lymphoid transcripts in donor-derived cells compared to controls. Surprisingly, recipient-derived cells also showed upregulation of myeloid- and erythroblast-related transcripts, indicating a skewing of the non–JAK2V617F-carrying recipient hematopoietic system toward an MPN-like phenotype. In addition, RNA-seq analysis of the BM stroma from JAK2V617F BMT recipients indicated significant loss of osteomesenchymal transcripts. Consistently, micro–computed tomography imaging indicated loss of trabecular bone. In sum, our results indicate that low-frequency MPN-driving cells in unconditioned recipients not only impact hematopoiesis-supporting stroma but also profoundly influence unmutated cells, uniquely altering their transcriptomic and phenotypic profiles. These observations are challenging our current understanding of the etiology and therapeutic approaches to MPNs and other CHIP-associated diseases.