HiJAKing the Hematopoietic System: A Low Variant Allele 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 (MPN). To determine the impact of the low frequency JAK2V617F clone on both the hematopoietic system and the bone marrow (BM) stroma, we developed a traceable murine JAK2V617F MPN model where the disease is induced in unconditioned bone marrow transplantation (BMT) recipients. Whole BMT was performed via a single tail vein injection of 5.0x106 cells into unconditioned C57BL/6 Ptprca CD45.1+ recipient mice using CD45.2+ donor cells carrying JAK2V617F isolated from a Poly I:C inducible MPN-like model. BMT resulted in a PV-like phenotype (elevated hematocrit and leukocytosis) with an average donor cell chimerism in peripheral blood of 2.74%. Eight months after BMT, RNA-seq analysis of whole 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 28-32 weeks post-BMT indicated significant loss of osteo-mesenchymal transcripts. Consistently, micro-CT imaging indicated loss of trabecular bone. Our model uncovers the impact of JAK2V617F donor cells on the host BM microenvironment and hematopoietic system, driving an MPN phenotype even with low donor cell chimerism within unconditioned recipients. The observation that BMT recipient’s hematopoietic cells, which do not carry JAK2V617F, acquire unique transcriptomic and phenotypic profiles suggests that the MPN clone not only impacts hematopoiesis-supporting stroma but profoundly influences unmutated cells, challenging our current understanding and therapeutic approaches to MPNs and other CHIP-associated diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE278496 | GEO | 2025/08/20

REPOSITORIES: GEO