{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,21]],"date-time":"2026-06-21T18:48:15Z","timestamp":1782067695918,"version":"3.54.5"},"reference-count":50,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2023,12,20]],"date-time":"2023-12-20T00:00:00Z","timestamp":1703030400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["3554\/1\u20103"],"award-info":[{"award-number":["3554\/1\u20103"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Oncology"],"published-print":{"date-parts":[[2024,2]]},"abstract":"<jats:p>Tyrosine\u2010protein kinase (janus kinase; JAK)\u2013signal transducer and activator of transcription (STAT) signaling plays a pivotal role in the development of myeloproliferative neoplasms (MPNs). Treatment with the potent JAK1\/JAK2\u2010specific inhibitor, ruxolitinib, significantly reduces tumor burden; however, ruxolitinib treatment does not fully eradicate the malignant clone. As the molecular basis for the disease persistence is not well understood, we set out to gain new insights by generating ruxolitinib\u2010resistant cell lines. Surprisingly, these cells harbor a 45\u2009kDa JAK2 variant (FERM\u2010JAK2) consisting of the N\u2010terminal FERM domain directly fused to the C\u2010terminal kinase domain in 80% of sublines resistant to ruxolitinib. At the molecular level, FERM\u2010JAK2 is able to directly bind and activate STAT5 in the absence of cytokine receptors. Furthermore, phosphorylation of activation\u2010loop tyrosines is dispensable for FERM\u2010JAK2\u2010mediated STAT5 activation and cellular transformation, in contrast to JAK2\u2010V617F. As a result, FERM\u2010JAK2 is highly resistant to several ATP\u2010competitive JAK2 inhibitors, whereas it is particularly sensitive to HSP90 inhibition. A murine model of FERM\u2010JAK2 leukemogenesis showed an accelerated MPN phenotype with pronounced splenomegaly. Notably, most current protocols for the monitoring of emerging JAK variants are unable to detect FERM\u2010JAK2, highlighting the urgent need for implementing next\u2010generation sequencing approaches in MPN patients receiving ruxolitinib.<\/jats:p>","DOI":"10.1002\/1878-0261.13566","type":"journal-article","created":{"date-parts":[[2023,12,18]],"date-time":"2023-12-18T01:09:25Z","timestamp":1702861765000},"page":"415-430","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A newly identified 45\u2010kDa JAK2 variant with an altered kinase domain structure represents a novel mode of JAK2 kinase inhibitor resistance"],"prefix":"10.1002","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-2977-3870","authenticated-orcid":false,"given":"Sivahari Prasad","family":"Gorantla","sequence":"first","affiliation":[{"name":"Department of Hematology and Oncology, Medical Center University of Schleswig\u2010Holstein  L\u00fcbeck Germany"},{"name":"Department of Internal Medicine I University Medical Center Freiburg  Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tony Andreas","family":"Mueller","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I University Medical Center Freiburg  Germany"},{"name":"Department of Internal Medicine I, Center for Molecular Medicine Cologne (CMMC) University of Cologne  Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinna","family":"Albers\u2010Leischner","sequence":"additional","affiliation":[{"name":"Department of Oncology, Hematology and Bone Marrow Transplantation with Section Pneumology, Hubertus Wald Comprehensive Cancer Center Hamburg University Medical Center Hamburg\u2010Eppendorf  Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Rudelius","sequence":"additional","affiliation":[{"name":"Department of Pathology University Hospital, LMU Munich  Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikolas","family":"von Bubnoff","sequence":"additional","affiliation":[{"name":"Department of Hematology and Oncology, Medical Center University of Schleswig\u2010Holstein  L\u00fcbeck Germany"},{"name":"Department of Internal Medicine I University Medical Center Freiburg  Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justus","family":"Duyster","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I University Medical Center Freiburg  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