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Gaucher disease is caused by genetic deficiency of acid \u03b2\u2010glucosidase, the natural substrates of which (\u03b2\u2010<jats:sc>d<\/jats:sc>\u2010glucosylceramide and \u03b2\u2010<jats:sc>d<\/jats:sc>\u2010glucosylsphingosine) accumulate, principally in macrophages. Mice with inducible deficiency of \u03b2\u2010glucosidase [Gba(<jats:styled-content style=\"fixed-case\">tm1Karl<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">tm1Karl<\/jats:styled-content>)Tg(<jats:styled-content style=\"fixed-case\">MX1<\/jats:styled-content>\u2010cre)<jats:styled-content style=\"fixed-case\">1Cgn<\/jats:styled-content>\/0] serve as an authentic model of human Gaucher disease; we have recently reported clonal B\u2010cell proliferation accompanied by monoclonal serum paraproteins and cognate tumours in these animals. To explore the relationship between B\u2010cell malignancy and the biochemical defect, we treated Gaucher mice with eliglustat tartrate (<jats:styled-content style=\"fixed-case\">GENZ<\/jats:styled-content> 112638), a potent and selective inhibitor of the first committed step in glycosphingolipid biosynthesis. Twenty\u2010two Gaucher mice received 300\u2009mg\/kg of <jats:styled-content style=\"fixed-case\">GENZ<\/jats:styled-content> 112638 daily for 3\u201310 months from 6 weeks of age. Plasma concentrations of \u03b2\u2010<jats:sc>d<\/jats:sc>\u2010glucosylceramide and the unacylated glycosphingolipid, \u03b2\u2010<jats:sc>d<\/jats:sc>\u2010glucosylsphingosine, declined. After administration of <jats:styled-content style=\"fixed-case\">GENZ<\/jats:styled-content> 112638 to Gaucher mice for 3\u201310 months, serum paraproteins were not detected and there was a striking reduction in the malignant lymphoproliferation: neither lymphomas nor plasmacytomas were found in animals that had received the investigational agent. In contrast, 14 out of 60 Gaucher mice without <jats:styled-content style=\"fixed-case\">GENZ<\/jats:styled-content> 112638 treatment developed these tumours; monoclonal paraproteins were detected in plasma from 18 of the 44 age\u2010matched mice with Gaucher disease that had not received <jats:styled-content style=\"fixed-case\">GENZ<\/jats:styled-content> 112638. Long\u2010term inhibition of glycosphingolipid biosynthesis suppresses the development of spontaneous B\u2010cell lymphoma and myeloma in Gaucher mice. Copyright \u00a9 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/path.4452","type":"journal-article","created":{"date-parts":[[2014,9,25]],"date-time":"2014-09-25T08:11:34Z","timestamp":1411632694000},"page":"113-124","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":74,"title":["Inhibition of <scp>UDP<\/scp>\u2010glucosylceramide synthase in mice prevents Gaucher disease\u2010associated B\u2010cell malignancy"],"prefix":"10.1002","volume":"235","author":[{"given":"Elena V","family":"Pavlova","sequence":"first","affiliation":[{"name":"Department of Medicine University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joy","family":"Archer","sequence":"additional","affiliation":[{"name":"Department of Veterinary Medicine University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Z Wang","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nick","family":"Dekker","sequence":"additional","affiliation":[{"name":"Academic Medical Centre  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes MFG","family":"Aerts","sequence":"additional","affiliation":[{"name":"Academic Medical Centre  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Karlsson","sequence":"additional","affiliation":[{"name":"Lund Stem Cell Centre Lund University Hospital  Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy M","family":"Cox","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Cambridge  Cambridge UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,12,10]]},"reference":[{"key":"e_1_2_7_2_1","unstructured":"RiesLAG HarkinsD KrapchoM et al.SEER Cancer Statistics Review 1975\u20132003[Internet].National Cancer Institute.Bethesda MD. 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