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Ruxolinitib is approved for the treatment of MF. Responses to ruxolitinib in MF are of limited duration. Unexpectedly, treatment of JAK2-V617F expressing cells with ruxolitinib causes paradoxical hyperphosphorylation of JAK2 at activation loop Tyr1007\/Tyr1008. The significance of ruxolitinib-induced JAK2 hyperphosphorylation is not well understood. We found that a ruxolitinib-resistant JAK2 variant (V617F\u2009+\u2009L983F) and a kinase dead mutant (JAK2-V617F\u2009+\u2009K882R) did not show paradoxical hyperphosphorylation after ruxolitinib treatment indicating that it is an intrinsic mechanism. Antibodies against pTyr1007\/1008 failed to immunoprecipitate native JAK2-V617F in the presence of ruxolitinib, although JAK2-V617F was hyperphosphorylated at these sites, suggesting that in the presence of ruxolitinib the JAK2 activation loop is buried within the kinase domain. This stabilization of the activation loop conformation resulted in the protection of pTyr1007\/1008 sites from phosphatases. Mutation of Arg975 and Lys999 to Ala reduced the phosphorylation at both Tyr1007\/Tyr1008 residues, and notably, ruxolitinib treatment did not lead to JAK2 hyperphosphorylation. Importantly, hyperphosphorylated JAK2 after ruxolitinib dissociation displayed excess rebound activation of STAT5 target gene PIM kinase. Our results suggest a novel mode of kinase regulation by modulating kinase activity through conformational changes induced by ruxolitinib.<\/jats:p>\n                  <jats:p>Subject categories: JAK2-V617F, Ruxolitinib, JAK2 hyperphosphorylation, Phosphatases action, PIM kinases<\/jats:p>","DOI":"10.1038\/s41375-025-02594-7","type":"journal-article","created":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T02:18:20Z","timestamp":1745374700000},"page":"1678-1691","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Ruxolitinib mediated paradoxical JAK2 hyperphosphorylation is due to the protection of activation loop tyrosines from phosphatases"],"prefix":"10.1038","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-2977-3870","authenticated-orcid":false,"given":"Sivahari P.","family":"Gorantla","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8960-5040","authenticated-orcid":false,"given":"Lorenz","family":"Oelschl\u00e4ger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0438-7972","authenticated-orcid":false,"given":"Gerin","family":"Prince","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmin","family":"Osius","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suresh Babu","family":"Kolluri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yamil","family":"Maluje","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anke","family":"F\u00e4hnrich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nancy","family":"Ernst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alanis","family":"Barbosa Gulde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf Joachim","family":"Ludwig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timo","family":"Gemoll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"Fliedner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5083-9838","authenticated-orcid":false,"given":"Wencke","family":"Walter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0196-2837","authenticated-orcid":false,"given":"Torsten","family":"Haferlach","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0566-4554","authenticated-orcid":false,"given":"Niklas","family":"Gebauer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4763-4521","authenticated-orcid":false,"given":"Hauke","family":"Busch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justus","family":"Duyster","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9593-8947","authenticated-orcid":false,"given":"Nikolas","family":"von Bubnoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,23]]},"reference":[{"key":"2594_CR1","doi-asserted-by":"publisher","first-page":"1144","DOI":"10.1038\/nature03546","volume":"434","author":"C James","year":"2005","unstructured":"James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C, et al. 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The remaining authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All the methods were performed in accordance with the relevant guidelines and regulations. The study was approved by the internal scientific review board of MLL. All patients had given written informed consent to the use of genetic and clinical data according to the Declaration of Helsinki.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}}]}}