Multiple myeloma and
B cell lymphoma are leading causes of death in
Gaucher's disease but the nature of the stimulus driving the often noted clonal expansion of
immunoglobulin-secreting B cells and cognate lymphoid
malignancy is unknown. We investigated the long-term development of B cell
malignancies in an authentic model of non-neuronopathic
Gaucher's disease in mice: selective deficiency of β-
glucocerebrosidase in haematopoietic cells [Gba(tm1Karl/tm1Karl)Tg(Mx1-cre)1Cgn/0, with excision of exons 9-11 of the murine GBA1 gene, is induced by
poly[I:C]. Mice with
Gaucher's disease showed visceral storage of β-
glucosylceramide and greatly elevated plasma β-
glucosylsphingosine [median 57.9 (range 19.8-159) nm; n = 39] compared with control mice from the same strain [median 0.56 (range 0.04-1.38) nm; n = 29] (p < 0.0001). Sporadic fatal
B cell lymphomas developed in 11 of 21 GD mice (6-24 months) but only two of eight control animals developed tumours by age 24 months. Unexpectedly, most mice with overt
lymphoma had absent or few Gaucher cells but local inflammatory macrophages were present. Eleven of 39 of Gaucher mice developed
monoclonal gammopathy, but in the control group only one animal of 25 had clonal
immunoglobulin abnormalities. Seven of 10 of the
B cell lymphomas were found to secrete a monoclonal
paraprotein and the
lymphomas stained intensely for pan-B cell markers; reactive T lymphocytes were also present in tumour tissue. In the Gaucher mouse strain, it was notable that, as in patients with this disease, CD138(+) plasma cells frequently surrounded splenic macrophages engorged with
glycosphingolipid. Our strain of mice, with inducible deficiency of β-
glucocerebrosidase in haematopoietic cells and a high frequency of sporadic lethal B cell
malignancies, faithfully recapitulates human
Gaucher's disease: it serves as a tractable model to investigate the putative role of bioactive
sphingolipids in the control of B cell proliferation and the pathogenesis of
myelomatosis-the most prevalent human
cancer associated with this disorder.