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: Elena V Pavlova, Joy Archer, Susan Wang, Nick Dekker, Johannes Mfg Aerts, Stefan Karlsson, Timothy M Cox
• Journal: The Journal of pathology (J Pathol) Vol. 235 Issue 1 Pg. 113-24 (Jan 2015) ISSN: 1096-9896 [Electronic] England
• PMID: 25256118 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Chemical References

• Pyrrolidines
• Uridine Diphosphate
• eliglustat
• Glucosyltransferases
• ceramide glucosyltransferase

Topics

• Animals
• Disease Models, Animal
• Female
• Gaucher Disease (complications, metabolism)
• Glucosyltransferases (antagonists & inhibitors, metabolism)
• Lymphoma, B-Cell (etiology, pathology)
• Male
• Mice
• Pyrrolidines (pharmacology)
• Uridine Diphosphate (metabolism)