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Here we demonstrate that inhibition of two proteasome\u2010associated <jats:styled-content style=\"fixed-case\">DUB<\/jats:styled-content>s (<jats:styled-content style=\"fixed-case\">USP<\/jats:styled-content>14 and <jats:styled-content style=\"fixed-case\">UCHL<\/jats:styled-content>5) with the small molecule <jats:styled-content style=\"fixed-case\">DUB<\/jats:styled-content> inhibitor b\u2010<jats:styled-content style=\"fixed-case\">AP<\/jats:styled-content>15, results in apoptosis of human Waldenstr\u00f6m macroglobulinaemia (<jats:styled-content style=\"fixed-case\">WM<\/jats:styled-content>) cell lines and primary patient\u2010derived <jats:styled-content style=\"fixed-case\">WM<\/jats:styled-content> tumour cells. Importantly, b\u2010<jats:styled-content style=\"fixed-case\">AP<\/jats:styled-content>15 produced proteotoxic stress and apoptosis in <jats:styled-content style=\"fixed-case\">WM<\/jats:styled-content> cells that have acquired resistance to the proteasome inhibitor bortezomib. <jats:italic>In silico<\/jats:italic> modelling identified protein residues that were critical for the binding of b\u2010<jats:styled-content style=\"fixed-case\">AP<\/jats:styled-content>15 with <jats:styled-content style=\"fixed-case\">USP<\/jats:styled-content>14 or <jats:styled-content style=\"fixed-case\">UCHL<\/jats:styled-content>5 and proteasome enzyme activity assays confirmed that b\u2010<jats:styled-content style=\"fixed-case\">AP<\/jats:styled-content>15 does not affect the proteolytic capabilities of the 20S proteasome \u03b2\u2010subunits. <jats:italic>In vitro<\/jats:italic> toxicity from b\u2010<jats:styled-content style=\"fixed-case\">AP<\/jats:styled-content>15 appeared to result from a build\u2010up of ubiquitinated proteins and activation of the endoplasmic reticulum stress response in <jats:styled-content style=\"fixed-case\">WM<\/jats:styled-content> cells, an effect that also disrupted the mitochondria. Focused transcriptome profiling of b\u2010<jats:styled-content style=\"fixed-case\">AP<\/jats:styled-content>15\u2010treated <jats:styled-content style=\"fixed-case\">WM<\/jats:styled-content> cells revealed modulation of several genes regulating cell stress and <jats:styled-content style=\"fixed-case\">NF<\/jats:styled-content>\u2010\u03baB signalling, the latter whose protein translocation and downstream target activation was reduced by b\u2010<jats:styled-content style=\"fixed-case\">AP<\/jats:styled-content>15 <jats:italic>in vitro<\/jats:italic>. This is the first report to define the effects and underlying mechanisms associated with inhibition of <jats:styled-content style=\"fixed-case\">USP<\/jats:styled-content>14 and <jats:styled-content style=\"fixed-case\">UCHL<\/jats:styled-content>5 <jats:styled-content style=\"fixed-case\">DUB<\/jats:styled-content> activity in <jats:styled-content style=\"fixed-case\">WM<\/jats:styled-content> tumour cells.<\/jats:p>","DOI":"10.1111\/bjh.13304","type":"journal-article","created":{"date-parts":[[2015,2,17]],"date-time":"2015-02-17T21:24:57Z","timestamp":1424208297000},"page":"377-390","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":60,"title":["Targeted inhibition of the deubiquitinating enzymes, <scp>USP<\/scp>14 and <scp>UCHL<\/scp>5, induces proteotoxic stress and apoptosis in <scp>W<\/scp>aldenstr\u00f6m macroglobulinaemia tumour 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