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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/4941599
- author
- Pavlova, Elena V.
; Archer, Joy
; Wang, Susan Z.
; Dekker, Nick
; Aerts, Johannes M. F. G.
; Karlsson, Stefan
LU
and Cox, Timothy M.
- organization
- publishing date
- 2015
- 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 Inc.
- external identifiers
-
- wos:000346189200010
- scopus:84916227639
- pmid:25256118
- 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
- 2016-04-01 10:18:01
- date last changed
- 2022-04-12 04:53:14
@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}},
keywords = {{Gaucher disease; glycosphingolipids; lymphoma; myeloma; UDP-glucosylceramide synthase; GBA1 deficiency; eliglustat}},
language = {{eng}},
number = {{1}},
pages = {{113--124}},
publisher = {{John Wiley & Sons Inc.}},
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}},
doi = {{10.1002/path.4452}},
volume = {{235}},
year = {{2015}},
}