{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T01:09:48Z","timestamp":1790125788750,"version":"4.0.1"},"reference-count":46,"publisher":"American Society of Hematology","issue":"1","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2019,1,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Alterations in the ubiquitin proteasome system (UPS) leave malignant cells in heightened cellular stress, making them susceptible to proteasome inhibition. However, given the limited efficacy of proteasome inhibitors in non-Hodgkin lymphoma (NHL), novel approaches to target the UPS are needed. Here, we show that TAK-243, the first small-molecule inhibitor of the ubiquitin activating enzyme (UAE) to enter clinical development, disrupts all ubiquitin signaling and global protein ubiquitination in diffuse large B-cell lymphoma (DLBCL) cells, thereby inducing endoplasmic reticulum (ER) stress and the unfolded protein response (UPR). Activation of the ER stress response protein kinase R (PKR)\u2013like ER kinase and phosphorylation of eukaryotic translation initiator factor 2\u03b1 led to upregulation of the proapoptotic molecule C\/EBP homologous protein and cell death across a panel of DLBCL cell lines independent of cell of origin. Concurrently, targeting UAE led to accumulation of Cdt1, a replication licensing factor, leading to DNA rereplication, checkpoint activation, and cell cycle arrest. MYC oncoprotein sensitized DLBCL cells to UAE inhibition; engineered expression of MYC enhanced while genetic MYC knockdown protected from TAK-243\u2013induced apoptosis. UAE inhibition demonstrated enhanced ER stress and UPR and increased potency compared with bortezomib in DLBCL cell lines. In vivo treatment with TAK-243 restricted the growth of xenografted DLBCL tumors, accompanied by reduced cell proliferation and apoptosis. Finally, primary patient-derived DLBCL cells, including those expressing aberrant MYC, demonstrated susceptibility to UAE inhibition. In sum, targeting UAE may hold promise as a novel therapeutic approach in NHL.<\/jats:p>","DOI":"10.1182\/bloodadvances.2018026880","type":"journal-article","created":{"date-parts":[[2019,1,7]],"date-time":"2019-01-07T21:47:36Z","timestamp":1546897656000},"page":"51-62","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":52,"title":["Targeting ubiquitin-activating enzyme induces ER stress\u2013mediated apoptosis in B-cell lymphoma cells"],"prefix":"10.1182","volume":"3","author":[{"given":"Scott","family":"Best","sequence":"first","affiliation":[{"name":"Knight Cancer Institute, Oregon Health & Science University, Portland, OR; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taylor","family":"Hashiguchi","sequence":"additional","affiliation":[{"name":"Knight Cancer Institute, Oregon Health & Science University, Portland, OR; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Kittai","sequence":"additional","affiliation":[{"name":"Knight Cancer Institute, Oregon Health & Science University, Portland, OR; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nur","family":"Bruss","sequence":"additional","affiliation":[{"name":"Knight Cancer Institute, Oregon Health & Science University, Portland, OR; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cody","family":"Paiva","sequence":"additional","affiliation":[{"name":"Knight Cancer Institute, Oregon Health & Science University, Portland, OR; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Craig","family":"Okada","sequence":"additional","affiliation":[{"name":"Knight Cancer Institute, Oregon Health & Science University, Portland, OR; 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