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Although clinically approved JAK inhibitors improve symptoms and outcomes in MPNs, remissions are rare, and mutant allele burden does not substantively change with chronic therapy. We hypothesized this is due to limitations of current JAK inhibitors to potently and specifically abrogate mutant JAK2 signaling. We therefore developed a conditionally inducible mouse model allowing for sequential activation, and then inactivation, of Jak2V617F from its endogenous locus using a combined Dre-rox\/Cre-lox dual-recombinase system. Jak2V617F deletion abrogates MPN features, induces depletion of mutant-specific hematopoietic stem\/progenitor cells, and extends overall survival to an extent not observed with pharmacologic JAK inhibition, including when cooccurring with somatic Tet2 loss. Our data suggest JAK2V617F represents the best therapeutic target in MPNs and demonstrate the therapeutic relevance of a dual-recombinase system to assess mutant-specific oncogenic dependencies in vivo.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>Current JAK inhibitors to treat myeloproliferative neoplasms are ineffective at eradicating mutant cells. We developed an endogenously expressed Jak2V617F dual-recombinase knock-in\/knock-out model to investigate Jak2V617F oncogenic reversion in vivo. Jak2V617F deletion abrogates MPN features and depletes disease-sustaining MPN stem cells, suggesting improved Jak2V617F targeting offers the potential for greater therapeutic efficacy.<\/jats:p>\n                    <jats:p>See related commentary by Celik and Challen, p. 701.<\/jats:p>\n                    <jats:p>This article is featured in Selected Articles from This Issue, p. 695<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-22-0952","type":"journal-article","created":{"date-parts":[[2024,1,17]],"date-time":"2024-01-17T07:42:42Z","timestamp":1705477362000},"page":"737-751","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Jak2V617F Reversible Activation Shows Its Essential Requirement in Myeloproliferative Neoplasms"],"prefix":"10.1158","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0339-4220","authenticated-orcid":false,"given":"Andrew J.","family":"Dunbar","sequence":"first","affiliation":[{"name":"1Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York."},{"name":"2Leukemia Service, Department of Medicine and Center for Hematologic Malignancies, Memorial Sloan Kettering Cancer Center, New York, New York."},{"name":"3Myeloproliferative Neoplasm-Research Consortium."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8294-8748","authenticated-orcid":false,"given":"Robert L.","family":"Bowman","sequence":"additional","affiliation":[{"name":"1Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1018-4400","authenticated-orcid":false,"given":"Young C.","family":"Park","sequence":"additional","affiliation":[{"name":"1Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-0830-3731","authenticated-orcid":false,"given":"Kavi","family":"O'Connor","sequence":"additional","affiliation":[{"name":"1Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5813-6504","authenticated-orcid":false,"given":"Franco","family":"Izzo","sequence":"additional","affiliation":[{"name":"4Weill Cornell Medical College of Cornell University, New York, New York."},{"name":"5New York Genome Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1869-6467","authenticated-orcid":false,"given":"Robert M.","family":"Myers","sequence":"additional","affiliation":[{"name":"4Weill Cornell Medical College of Cornell University, New York, New York."},{"name":"5New York Genome Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4540-8339","authenticated-orcid":false,"given":"Abdul","family":"Karzai","sequence":"additional","affiliation":[{"name":"1Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-4495-5070","authenticated-orcid":false,"given":"Zachary","family":"Zaroogian","sequence":"additional","affiliation":[{"name":"1Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1816-6119","authenticated-orcid":false,"given":"Won Jun","family":"Kim","sequence":"additional","affiliation":[{"name":"1Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6683-1892","authenticated-orcid":false,"given":"In\u00e9s","family":"Fern\u00e1ndez-Maestre","sequence":"additional","affiliation":[{"name":"1Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York."},{"name":"6Louis V. 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