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.