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Mol. Life Sci."],"published-print":{"date-parts":[[2021,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Signaling via the B-cell receptor (BCR) is a key driver and therapeutic target in chronic lymphocytic leukemia (CLL). BCR stimulation of CLL cells induces expression of eIF4A, an initiation factor important for translation of multiple oncoproteins, and reduces expression of PDCD4, a natural inhibitor of eIF4A, suggesting that eIF4A may be a critical nexus controlling protein expression downstream of the BCR in these cells. We, therefore, investigated the effect of eIF4A inhibitors (eIF4Ai) on BCR-induced responses. We demonstrated that eIF4Ai (silvestrol and rocaglamide A) reduced anti-IgM-induced global mRNA translation in CLL cells and also inhibited accumulation of MYC and MCL1, key drivers of proliferation and survival, respectively, without effects on upstream signaling responses (ERK1\/2 and AKT phosphorylation). Analysis of normal na\u00efve and non-switched memory B cells, likely counterparts of the two main subsets of CLL, demonstrated that basal RNA translation was higher in memory B cells, but was similarly increased and susceptible to eIF4Ai-mediated inhibition in both. We probed the fate of\n                    <jats:italic>MYC<\/jats:italic>\n                    mRNA in eIF4Ai-treated CLL cells and found that eIF4Ai caused a profound accumulation of\n                    <jats:italic>MYC<\/jats:italic>\n                    mRNA in anti-IgM treated cells. This was mediated by\n                    <jats:italic>MYC<\/jats:italic>\n                    mRNA stabilization and was not observed for\n                    <jats:italic>MCL1<\/jats:italic>\n                    mRNA. Following drug wash-out,\n                    <jats:italic>MYC<\/jats:italic>\n                    mRNA levels declined but without substantial MYC protein accumulation, indicating that stabilized\n                    <jats:italic>MYC<\/jats:italic>\n                    mRNA remained blocked from translation. In conclusion, BCR-induced regulation of eIF4A may be a critical signal-dependent nexus for therapeutic attack in CLL and other B-cell malignancies, especially those dependent on MYC and\/or MCL1.\n                  <\/jats:p>","DOI":"10.1007\/s00018-021-03910-x","type":"journal-article","created":{"date-parts":[[2021,8,16]],"date-time":"2021-08-16T10:04:07Z","timestamp":1629108247000},"page":"6337-6349","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":33,"title":["Targeted inhibition of eIF4A suppresses B-cell receptor-induced translation and expression of MYC and MCL1 in chronic lymphocytic leukemia cells"],"prefix":"10.1007","volume":"78","author":[{"given":"Sarah","family":"Wilmore","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karly-Rai","family":"Rogers-Broadway","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joe","family":"Taylor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Lemm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Fell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Freda K.","family":"Stevenson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Forconi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew J.","family":"Steele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Coldwell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9232-5691","authenticated-orcid":false,"given":"Graham","family":"Packham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison","family":"Yeomans","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,8,16]]},"reference":[{"issue":"4","key":"3910_CR1","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1016\/j.cell.2009.01.042","volume":"136","author":"N Sonenberg","year":"2009","unstructured":"Sonenberg N, Hinnebusch AG (2009) Regulation of translation initiation in eukaryotes: mechanisms and biological targets. 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AJS holds stock in Portola Pharmaceuticals. All other authors have no relevant disclosures.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}},{"value":"The study was approved by the Institutional Review Boards at the University of Southampton (REC: H228\/02\/t).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}},{"value":"All patients provided written informed consent.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"Not applicable.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}}]}}