HiJAKing the Hematopoietic System: A Low-Frequency JAK2V617F Clone Drives Myeloproliferative Neoplasm Pathology Open Access

• Low-frequency of JAK2V617F clone drives an MPN-like disease in unconditioned bone marrow transplantation recipients

• Transplanted JAK2V617F clone profoundly impacts hematopoietic and stromal non-mutated bystander cells

JAK2V617F is one of the most common mutations in clonal hematopoiesis of indeterminate potential (CHIP) and a major driver of myeloproliferative neoplasms (MPN). To determine the impact of a low-frequency of JAK2V617F clone on both the hematopoietic system and the bone marrow (BM) stroma, we developed a traceable murine MPN model, where the whole BM transplantation (BMT) was performed using CD45.2 5.0x106 JAK2V617F donor cells into unconditioned CD45.1 recipient mice. BMT recipients developed a polycythemia vera (PV)-like phenotype (elevated hematocrit and leukocytosis) with a 2.7% average donor cell chimerism in peripheral blood. Eight months post-BMT, RNA-seq analysis of the BM sorted according to CD45.1/CD45.2 expression, showed significant upregulation of early erythroblast- and myeloid cell-specific transcripts, as well as 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 towards an MPN-like phenotype. In addition, RNA-seq analysis of the BM stroma from JAK2V617F BMT recipients indicated significant loss of osteo-mesenchymal transcripts. Consistently, micro-CT imaging indicated loss of trabecular bone. In sum, our results indicate that the low frequency MPN-driving cells in unconditioned recipients not only impact hematopoiesis-supporting stroma but profoundly influences unmutated cells, uniquely altering their transcriptomic and phenotypic profiles. These observations are challenging our current understanding of etiology and therapeutic approaches to MPNs and other CHIP-associated diseases.