Jak2(V617F) reversible activation shows its essential requirement in myeloproliferative neoplasms Journal Article
| Authors: | Dunbar, A. J.; Bowman, R. L.; Park, Y. C.; O'Connor, K.; Izzo, F.; Myers, R. M.; Karzai, A.; Zaroogian, Z.; Kim, W. J.; Fernandez-Maestre, I.; Waarts, M. R.; Nazir, A.; Xiao, W.; Codilupi, T.; Brodsky, M.; Farina, M.; Cai, L.; Cai, S. F.; Wang, B.; An, W.; Yang, J. L.; Mowla, S.; Eisman, S. E.; Somasundara, A. V. H.; Glass, J. L.; Mishra, T.; Houston, R.; Guzzardi, E.; Martinez Benitez, A. R.; Viny, A. D.; Koche, R. P.; Meyer, S. C.; Landau, D. A.; Levine, R. L. |
| Article Title: | Jak2(V617F) reversible activation shows its essential requirement in myeloproliferative neoplasms |
| Abstract: | Gain-of-function mutations activating JAK/STAT signaling are seen in the majority of patients with myeloproliferative neoplasms (MPN), most commonly JAK2(V617F). 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 Jak2(V617F) from its endogenous locus using a combined Dre-rox/Cre-lox dual-recombinase system. Jak2(V617F) 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 JAK2(V617F) 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.<br /> Significance: Current JAK inhibitors to treat myeloproliferative neoplasms are ineffective at eradicating mutant cells. We developed an endogenously expressed Jak2(V617F) dual-recombinase knock-in/knock-out model to investigate Jak2(V617F) oncogenic reversion in vivo. Jak2(V617F) deletion abrogates MPN features and depletes disease-sustaining MPN stem cells, suggesting improved Jak2(V617F) targeting offers the potential for greater therapeutic efficacy. |
| Keywords: | mice; efficacy; cells; accessibility; leads; hematopoietic stem; ruxolitinib; jak2v617f expression; tet2 loss; ii jak2 inhibitor |
| Journal Title: | Cancer Discovery |
| Volume: | 14 |
| Issue: | 5 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2024-05-01 |
| Start Page: | 737 |
| End Page: | 751 |
| Language: | English |
| ACCESSION: | WOS:001225915900001 |
| DOI: | 10.1158/2159-8290.Cd-22-0952 |
| PROVIDER: | wos |
| PMCID: | PMC11061606 |
| PUBMED: | 38230747 |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. Corresponding MSK author is Ross L. Levine -- Source: Wos |
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