{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Dunbar AJ"],"funding":["Swiss National Science Foundation","National Heart, Lung, and Blood Institute","NHLBI NIH HHS","National Cancer Institute","NHGRI NIH HHS","NCI NIH HHS","NINDS NIH HHS","Damon Runyon Cancer Research Foundation","National Institute of General Medical Sciences","NIGMS NIH HHS","Leukemia and Lymphoma Society"],"pagination":["737-751"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11061606"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["14(5)"],"pubmed_abstract":["Gain-of-function mutations activating JAK/STAT signaling are seen in the majority of patients with myeloproliferative neoplasms (MPN), most commonly JAK2V617F. 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.<h4>Significance</h4>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. See related commentary by Celik and Challen, p. 701. This article is featured in Selected Articles from This Issue, p. 695."],"journal":["Cancer discovery"],"pubmed_title":["Jak2V617F Reversible Activation Shows Its Essential Requirement in Myeloproliferative Neoplasms."],"pmcid":["PMC11061606"],"funding_grant_id":["T32 CA009207","R37 CA286857","P01 CA1086","K08 CA215317","P01 CA108671","K99CA248460","R01 HL157387","P30 CA008748","R01 HL145283","K08 CA230172","K08 HL169905","R01HL157387-01A1","R35 CA197594","K08 CA267058","T32 GM007739","RM1 HG011014","181357","PST-24-19","K99 CA248460","161145","R00 CA248460","F99 CA284253","R01HL145283","P50 CA254838","UG3 NS132139","F99 CA274656","K08 CA241371","T32GM007739","R33 CA267219"],"pubmed_authors":["Brodsky M","Guzzardi E","O'Connor K","Eisman SE","Nazir A","Wang B","Levine RL","Cai L","Houston R","Meyer SC","Park YC","Kim WJ","Fernandez-Maestre I","Zaroogian Z","Waarts MR","An W","Myers RM","Farina M","Mishra T","Martinez Benitez AR","Koche RP","Glass JL","Karzai A","Xiao W","Izzo F","Yang JL","Viny AD","Cai SF","Mowla S","Dunbar AJ","Bowman RL","Codilupi T","Hanasoge Somasundara AV","Landau DA"],"additional_accession":[]},"is_claimable":false,"name":"Jak2V617F Reversible Activation Shows Its Essential Requirement in Myeloproliferative Neoplasms.","description":"Gain-of-function mutations activating JAK/STAT signaling are seen in the majority of patients with myeloproliferative neoplasms (MPN), most commonly JAK2V617F. 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.<h4>Significance</h4>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. See related commentary by Celik and Challen, p. 701. This article is featured in Selected Articles from This Issue, p. 695.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 May","modification":"2026-06-01T11:31:47.141Z","creation":"2026-04-08T11:53:27.163Z"},"accession":"S-EPMC11061606","cross_references":{"pubmed":["38230747"],"doi":["10.1158/2159-8290.CD-22-0952"]}}