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JAK2 inhibitors provide clinical benefits, but compensatory activation of MAPK pathway signaling impedes efficacy. We hypothesized that dual targeting of JAK2 and ERK1\/2 could enhance clone control and therapeutic efficacy. We employed genetic and pharmacologic targeting of ERK1\/2 in <jats:italic>Jak2<\/jats:italic>V617F MPN mice, cells and patient clinical isolates. Competitive transplantations of <jats:italic>Jak2<\/jats:italic>V617F vs. wild-type bone marrow (BM) showed that ERK1\/2 deficiency in hematopoiesis mitigated MPN features and reduced the <jats:italic>Jak2<\/jats:italic>V617F clone in blood and hematopoietic progenitor compartments. ERK1\/2 ablation combined with JAK2 inhibition suppressed MAPK transcriptional programs, normalized cytoses and promoted clone control suggesting dual JAK2\/ERK1\/2 targeting as enhanced corrective approach. Combined pharmacologic JAK2\/ERK1\/2 inhibition with ruxolitinib and ERK inhibitors reduced proliferation of <jats:italic>Jak2<\/jats:italic>V617F cells and corrected erythrocytosis and splenomegaly of <jats:italic>Jak2<\/jats:italic>V617F MPN mice. Longer-term treatment was able to induce clone reductions. BM fibrosis was significantly decreased in <jats:italic>MPL<\/jats:italic>W515L-driven MPN to an extent not seen with JAK2 inhibitor monotherapy. Colony formation from <jats:italic>JAK2<\/jats:italic>V617F patients\u2019 CD34<jats:sup>+<\/jats:sup> blood and BM was dose-dependently inhibited by combined JAK2\/ERK1\/2 inhibition in PV, ET, and MF subsets. Overall, we observed that dual targeting of JAK2 and ERK1\/2 was able to enhance therapeutic efficacy suggesting a novel treatment approach for MPN.<\/jats:p>","DOI":"10.1038\/s41375-021-01391-2","type":"journal-article","created":{"date-parts":[[2021,9,3]],"date-time":"2021-09-03T16:18:41Z","timestamp":1630685921000},"page":"2875-2884","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Dual targeting of JAK2 and ERK interferes with the myeloproliferative neoplasm clone and enhances therapeutic efficacy"],"prefix":"10.1038","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0148-6423","authenticated-orcid":false,"given":"Sime","family":"Brkic","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1549-8932","authenticated-orcid":false,"given":"Simona","family":"Stivala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Santopolo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jakub","family":"Szybinski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Jungius","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jakob R.","family":"Passweg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitrios","family":"Tsakiris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Dirnhofer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregor","family":"Hutter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4004-3473","authenticated-orcid":false,"given":"Katharina","family":"Leonards","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9616-2092","authenticated-orcid":false,"given":"Heidi E. 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GH is co-founder and shareholder of Incephalo AG, received consulting honoraria from Novartis and B. Braun AG, and received research grants from Novartis Research Foundation. BGN is the co-founder of Northern Biologics, Ltd, Navire Pharmaceuticals, and Jengu Therapeutics and has an equity interest in each. He also receives consulting fees from the latter two companies. In addition, he is on the SAB of Arvinas, Inc., for which receives consulting fees and equity. His spouse holds shares in Amgen and during the course of this work also held shares in Arvinas, Moderna, and Regeneron. RLL is on the supervisory board of Qiagen and is a scientific advisor to Loxo, Imago, C4 Therapeutics and Isoplexis, which each include an equity interest. He receives research support from and consulted for Celgene and Roche, he has received research support from Prelude Therapeutics, and he has consulted for Incyte, Novartis, Morphosys and Janssen. He has received honoraria from Lilly and Amgen for invited lectures and from Gilead for grant reviews. All other authors do not have any competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}