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In particular, patients with\n                    <jats:italic>t<\/jats:italic>\n                    (4;14)-positive disease have worse prognosis compared to other MM subtypes. Herein, we demonstrated that\n                    <jats:italic>t<\/jats:italic>\n                    (4;14)-positive cells are highly dependent on the mevalonate (MVA) pathway for survival. Moreover, we showed that this metabolic vulnerability is immediately actionable, as inhibiting the MVA pathway with a statin preferentially induced apoptosis in\n                    <jats:italic>t<\/jats:italic>\n                    (4;14)-positive cells. In response to statin treatment,\n                    <jats:italic>t<\/jats:italic>\n                    (4;14)-positive cells activated the integrated stress response (ISR), which was augmented by co-treatment with bortezomib, a proteasome inhibitor. We identified that\n                    <jats:italic>t<\/jats:italic>\n                    (4;14)-positive cells depend on the MVA pathway for the synthesis of geranylgeranyl pyrophosphate (GGPP), as exogenous GGPP fully rescued statin-induced ISR activation and apoptosis. Inhibiting protein geranylgeranylation similarly induced the ISR in\n                    <jats:italic>t<\/jats:italic>\n                    (4;14)-positive cells, suggesting that this subtype of MM depends on GGPP, at least in part, for protein geranylgeranylation. Notably, fluvastatin treatment synergized with bortezomib to induce apoptosis in\n                    <jats:italic>t<\/jats:italic>\n                    (4;14)-positive cells and potentiated the anti-tumor activity of bortezomib in vivo. Our data implicate the\n                    <jats:italic>t<\/jats:italic>\n                    (4;14) translocation as a biomarker of statin sensitivity and warrant further clinical evaluation of a statin in combination with bortezomib for the treatment of\n                    <jats:italic>t<\/jats:italic>\n                    (4;14)-positive disease.\n                  <\/jats:p>","DOI":"10.1038\/s41375-020-0962-2","type":"journal-article","created":{"date-parts":[[2020,7,14]],"date-time":"2020-07-14T12:04:26Z","timestamp":1594728266000},"page":"796-808","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":32,"title":["The mevalonate pathway is an actionable vulnerability of t(4;14)-positive multiple myeloma"],"prefix":"10.1038","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9580-5105","authenticated-orcid":false,"given":"Joseph","family":"Longo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9395-8450","authenticated-orcid":false,"given":"Petr","family":"Smirnov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihua","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Branchard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4744-2960","authenticated-orcid":false,"given":"Jenna E.","family":"van Leeuwen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3942-1369","authenticated-orcid":false,"given":"Jonathan D.","family":"Licht","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7684-0079","authenticated-orcid":false,"given":"Benjamin","family":"Haibe-Kains","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9266-7157","authenticated-orcid":false,"given":"David W.","family":"Andrews","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4375-7399","authenticated-orcid":false,"given":"Jonathan J.","family":"Keats","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trevor J.","family":"Pugh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suzanne","family":"Trudel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8133-5459","authenticated-orcid":false,"given":"Linda Z.","family":"Penn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,7,14]]},"reference":[{"key":"962_CR1","doi-asserted-by":"publisher","first-page":"5611","DOI":"10.1038\/sj.onc.1204641","volume":"20","author":"PL Bergsagel","year":"2001","unstructured":"Bergsagel PL, Kuehl WM. 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