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Inhibition of UDP-glucosylceramide synthase in mice prevents Gaucher disease-associated B-cell malignancy

Pavlova, Elena V.; Archer, Joy; Wang, Susan Z.; Dekker, Nick; Aerts, Johannes M. F. G.; Karlsson, Stefan LU and Cox, Timothy M. (2015) In Journal of Pathology 235(1). p.113-124
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 -glucosidase, the natural substrates of which (-d-glucosylceramide and -d-glucosylsphingosine) accumulate, principally in macrophages. Mice with inducible deficiency of -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... (More)
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 -glucosidase, the natural substrates of which (-d-glucosylceramide and -d-glucosylsphingosine) accumulate, principally in macrophages. Mice with inducible deficiency of -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 300mg/kg of GENZ 112638 daily for 3-10 months from 6 weeks of age. Plasma concentrations of -d-glucosylceramide and the unacylated glycosphingolipid, -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. Copyright (c) 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. (Less)
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author
organization
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type
Contribution to journal
publication status
published
subject
keywords
Gaucher disease, glycosphingolipids, lymphoma, myeloma, UDP-glucosylceramide synthase, GBA1 deficiency, eliglustat
in
Journal of Pathology
volume
235
issue
1
pages
113 - 124
publisher
John Wiley & Sons
external identifiers
  • wos:000346189200010
  • scopus:84916227639
ISSN
0022-3417
DOI
10.1002/path.4452
language
English
LU publication?
yes
id
990875d6-a5e3-497e-a1aa-53d653f59f62 (old id 4941599)
date added to LUP
2015-02-03 07:07:03
date last changed
2017-11-19 03:08:49
@article{990875d6-a5e3-497e-a1aa-53d653f59f62,
  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 -glucosidase, the natural substrates of which (-d-glucosylceramide and -d-glucosylsphingosine) accumulate, principally in macrophages. Mice with inducible deficiency of -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 300mg/kg of GENZ 112638 daily for 3-10 months from 6 weeks of age. Plasma concentrations of -d-glucosylceramide and the unacylated glycosphingolipid, -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. Copyright (c) 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.},
  author       = {Pavlova, Elena V. and Archer, Joy and Wang, Susan Z. and Dekker, Nick and Aerts, Johannes M. F. G. and Karlsson, Stefan and Cox, Timothy M.},
  issn         = {0022-3417},
  keyword      = {Gaucher disease,glycosphingolipids,lymphoma,myeloma,UDP-glucosylceramide synthase,GBA1 deficiency,eliglustat},
  language     = {eng},
  number       = {1},
  pages        = {113--124},
  publisher    = {John Wiley & Sons},
  series       = {Journal of Pathology},
  title        = {Inhibition of UDP-glucosylceramide synthase in mice prevents Gaucher disease-associated B-cell malignancy},
  url          = {http://dx.doi.org/10.1002/path.4452},
  volume       = {235},
  year         = {2015},
}