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.

Clonal Immunoglobulin against Lysolipids in the Origin of Myeloma

“…These data are also consistent with recent findings regarding a reduced risk of B-cell cancers with substrate reduction in another model of Gaucher’s disease. 23 …”

A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments

“…Interestingly, mice bearing large tumors had less GlcCer and glucosylsphingosine accumulation than those with small tumors. In this model, the monoclonal protein disappeared from mice treated with eliglustat; moreover, a striking reduction in lymphoproliferation was observed, with no plasmocytoma or lymphoma [68]. A more recent study on monoclonal immunoglobulin (Ig) in GD showed that in 17 of 20 patients with GD and six of six Gaucher mice, the clonal Ig was specific for glucosylsphingosine.…”

Lyso-glycosphingolipid abnormalities in different murine models of lysosomal storage disorders

“…In the case of GBA-deficient Limp2 −/− mice, plasma GlySph was 4-fold increased, but no clear abnormalities in other lyso-GSLs are detected. Insufficient plasma of GD1 mice was available for complete lipid analysis following that of GlcSph which was found to be 170-fold elevated [26]. In the case of Krabbe mice, plasma galactosylsphingosine (GalSph, more than 90% of total GlySph) was about~12-fold increased, but other lyso-GSLs appeared normal.…”

“…Consequently, it remains unclear whether the GlcSph contributes to the symptoms observed in GD patients, such as occurrence of hemolysis, multinucleated macrophages, neuropathology, growth retardation, bone deterioration and chronic low grade inflammation [6]. Recent investigations by Cox and coworkers have revealed an intriguing correlation between the occurrence of lymphoma in Gba tm1Karl/tm1Karl Tg(Mx1-cre)1Cgn/0 mice and GlcSph levels [26,45]. Currently a direct role for elevated GlcSph in the symptomatology of GD has not yet been unequivocally demonstrated.…”