In Vivo Monitoring of Polycythemia Vera Development Reveals Carbonic Anhydrase 1 as a Potent Therapeutic Target

Current murine models of myeloproliferative neoplasms (MPN s) cannot examine how MPN s progress from a single bone marrow source to the entire hematopoietic system. Thus, using transplantation of knock-in JAK2V617F hematopoietic cells into a single irradiated leg, we show development of polycythemia vera (PV) from a single anatomic site in immunocompetent mice. Barcode experiments reveal that grafted JAK2V617F stem/progenitor cells migrate from the irra-diated leg to nonirradiated organs such as the contralateral leg and spleen, which is strictly required for development of PV. Mutant cells colonizing the nonirradiated leg effi ciently induce PV in noncon-ditioned recipient mice and contain JAK2V617F hematopoietic stem/progenitor cells that express high levels of carbonic anhydrase 1 (CA1), a peculiar feature also found in CD34+ cells from patients with PV. Finally, genetic and pharmacologic inhibition of CA1 effi ciently suppresses PV development and progression in mice and decrease s PV patients' erythroid progenitors , strengthening CA1 as a potent therapeutic target for PV.SIGNIFICANCE: Follow-up of hematopoietic malignancies from their initiating anatomic site is cru-cial for understanding their development and discovering new therapeutic avenues. We developed such an approach, used it to characterize PV progression, and identifi ed CA1 as a promising thera-peutic target of PV.