{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T20:33:21Z","timestamp":1790973201553,"version":"4.1.0"},"reference-count":55,"publisher":"Rockefeller University Press","issue":"2","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2012,2,13]]},"abstract":"<jats:p>Enzymatic inhibitors of Janus kinase 2 (JAK2) are in clinical development for the treatment of myeloproliferative neoplasms (MPNs), B cell acute lymphoblastic leukemia (B-ALL) with rearrangements of the cytokine receptor subunit cytokine receptor\u2013like factor 2 (CRLF2), and other tumors with constitutive JAK2 signaling. In this study, we identify G935R, Y931C, and E864K mutations within the JAK2 kinase domain that confer resistance across a panel of JAK inhibitors, whether present in cis with JAK2 V617F (observed in MPNs) or JAK2 R683G (observed in B-ALL). G935R, Y931C, and E864K do not reduce the sensitivity of JAK2-dependent cells to inhibitors of heat shock protein 90 (HSP90), which promote the degradation of both wild-type and mutant JAK2. HSP90 inhibitors were 100\u20131,000-fold more potent against CRLF2-rearranged B-ALL cells, which correlated with JAK2 degradation and more extensive blockade of JAK2\/STAT5, MAP kinase, and AKT signaling. In addition, the HSP90 inhibitor AUY922 prolonged survival of mice xenografted with primary human CRLF2-rearranged B-ALL further than an enzymatic JAK2 inhibitor. Thus, HSP90 is a promising therapeutic target in JAK2-driven cancers, including those with genetic resistance to JAK enzymatic inhibitors.<\/jats:p>","DOI":"10.1084\/jem.20111694","type":"journal-article","created":{"date-parts":[[2012,1,24]],"date-time":"2012-01-24T05:26:28Z","timestamp":1327382788000},"page":"259-273","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":143,"title":["Genetic resistance to JAK2 enzymatic inhibitors is overcome by HSP90 inhibition"],"prefix":"10.1084","volume":"209","author":[{"given":"Oliver","family":"Weigert","sequence":"first","affiliation":[{"name":"Medical Oncology Departments of 1 , 2 , 3 , and the 4"},{"name":"Cancer Biology Departments of 1 , 2 , 3 , and the 4"},{"name":"Pediatric Oncology Departments of 1 , 2 , 3 , and the 4"},{"name":"Lurie Family Imaging Center, Dana-Farber Cancer Institute, Boston, MA 02115 Departments of 1 , 2 , 3 , and the 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