title: Inhibition of UDP-glucosylceramide synthase in mice prevents Gaucher disease-associated B-cell malignancy.
abstract: Clonal B-cell proliferation is a frequent manifestation of Gaucher disease - a sphingolipidosis associated with a high risk of multiple myeloma and non-Hodgkin lymphoma. Gaucher disease is caused by genetic deficiency of acid β-glucosidase, the natural substrates of which (β-d-glucosylceramide and β-d-glucosylsphingosine) accumulate, principally in macrophages. Mice with inducible deficiency of β-glucosidase [Gba(tm1Karl/tm1Karl)Tg(MX1-cre)1Cgn/0] serve as an authentic model of human Gaucher disease; we have recently reported clonal B-cell proliferation accompanied by monoclonal serum paraproteins and cognate tumours in these animals. To explore the relationship between B-cell malignancy and the biochemical defect, we treated Gaucher mice with eliglustat tartrate (GENZ 112638), a potent and selective inhibitor of the first committed step in glycosphingolipid biosynthesis. Twenty-two Gaucher mice received 300 mg/kg of GENZ 112638 daily for 3-10 months from 6 weeks of age. Plasma concentrations of β-d-glucosylceramide and the unacylated glycosphingolipid, β-d-glucosylsphingosine, declined. After administration of GENZ 112638 to Gaucher mice for 3-10 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 GENZ 112638 treatment developed these tumours; monoclonal paraproteins were detected in plasma from 18 of the 44 age-matched mice with Gaucher disease that had not received GENZ 112638. Long-term inhibition of glycosphingolipid biosynthesis suppresses the development of spontaneous B-cell lymphoma and myeloma in Gaucher mice.
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge, UK.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Pavlova
authors.forename: Joy
authors.initials: J
authors.lastname: Archer
authors.forename: Susan
authors.initials: S
authors.lastname: Wang
authors.forename: Nick
authors.initials: N
authors.lastname: Dekker
authors.forename: Johannes Mfg
authors.initials: JM
authors.lastname: Aerts
authors.forename: Stefan
authors.initials: S
authors.lastname: Karlsson
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Cox
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005776:Gaucher Disease / Q000150:complications* / Q000378:metabolism; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016393:Lymphoma, B-Cell / Q000209:etiology / Q000473:pathology*; D008297:Male; D051379:Mice; D011759:Pyrrolidines / Q000494:pharmacology*; D014530:Uridine Diphosphate / Q000378:metabolism
chemical_list: D011759:Pyrrolidines; D014530:Uridine Diphosphate; C522917:eliglustat; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase
keywords: GBA1 deficiency; Gaucher disease; UDP-glucosylceramide synthase; eliglustat; glycosphingolipids; lymphoma; myeloma