{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T18:41:11Z","timestamp":1790707271006,"version":"4.1.0"},"reference-count":45,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2019,8,26]],"date-time":"2019-08-26T00:00:00Z","timestamp":1566777600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100008373","name":"Takeda Pharmaceutical Company","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008373","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Br J Haematol"],"published-print":{"date-parts":[[2020,1]]},"abstract":"<jats:title>Summary<\/jats:title><jats:p>Ixazomib activity and transcriptomic analyses previously established in T cell (TCL) and Hodgkin (HL) lymphoma models predicted synergistic activity for histone deacetylase (HDAC) inhibitory combination. In this present study, we determined the mechanistic basis for ixazomib combination with the HDAC inhibitor, belinostat, in HL and TCL cells lines (ixazomib\u2010sensitive\/resistant clones) and primary tumour cells. In ixazomib\u2010treated TCL and HL cells, transient inhibition followed by full recovery of proteasomal activity observed was accompanied by induction of proteasomal gene expression with <jats:italic>NFE2L2<\/jats:italic> (also termed <jats:italic>NRF2<\/jats:italic>) <jats:italic>as<\/jats:italic> a prominent upstream regulator. Downregulation of both <jats:italic>NFE2L2<\/jats:italic> and proteasomal gene expression (validated by quantitative real time polymerase chain reaction) occurred with belinostat treatment in Jurkat and L428 cells. In addition, CRISPR\/Cas9 mediated knockdown of <jats:italic>NFE2L2<\/jats:italic> in Jurkat cells resulted in a significant decrease in cell viability with ixazomib compared with untreated control cells. Using transcriptomic and proteasomal activity evaluation of ixazomib, belinostat, or ixazomib\u00a0+\u00a0belinostat treated cells, we observed that <jats:italic>NFE2L2<\/jats:italic>, proteasome gene expression and functional recovery were abrogated by ixazomib\u00a0+\u00a0belinostat combination, resulting in synergistic drug activity in ixazomib\u2010sensitive and \u2010resistant cell lines and primary cells. Altogether, these results suggest that the synergistic activity of ixazomib\u00a0+\u00a0belinostat is mediated via inhibition <jats:italic>NFE2L2<\/jats:italic>\u2010dependent proteasomal recovery and extended proteasomal inhibition culminating in increased cell death.<\/jats:p>","DOI":"10.1111\/bjh.16160","type":"journal-article","created":{"date-parts":[[2019,8,27]],"date-time":"2019-08-27T05:13:59Z","timestamp":1566882839000},"page":"295-308","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Combinatorial ixazomib and belinostat therapy induces NFE2L2\u2010dependent apoptosis in Hodgkin and T\u2010cell lymphoma"],"prefix":"10.1111","volume":"188","author":[{"suffix":"Jr","given":"Frank C.","family":"Passero","sequence":"first","affiliation":[{"name":"Department of Medicine University of Rochester Medical Center Rochester NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dashnamoorthy","family":"Ravi","sequence":"additional","affiliation":[{"name":"Division of Blood Disorders Rutgers Cancer Institute of New Jersey New Brunswick NJ USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. 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