Targeting EXT1 reveals a crucial role for heparan sulfate in the growth of multiple myeloma

Expression of the heparan sulfate proteoglycan syndecan-1 is a hallmark of both normal and multiple myeloma (MM) plasma cells. Syndecan-1 could affect plasma cell fate by strengthening integrin-mediated adhesion via its core protein and/or by accommodating and presenting soluble factors via its HS s...

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Bibliographic Details
Published in:Blood 2010-01, Vol.115 (3), p.601-604
Main Authors: Reijmers, Rogier M., Groen, Richard W.J., Rozemuller, Henk, Kuil, Annemieke, de Haan-Kramer, Anneke, Csikós, Tamás, Martens, Anton C.M., Spaargaren, Marcel, Pals, Steven T.
Format: Article
Language:English
Subjects:
Animals
Antineoplastic Combined Chemotherapy Protocols - administration & dosage
Antineoplastic Combined Chemotherapy Protocols - pharmacology
Biological and medical sciences
Cell Line, Tumor
Cell Proliferation - drug effects
DNA-Binding Proteins - genetics
Doxycycline - administration & dosage
Drug Delivery Systems
Gene Targeting
Hematologic and hematopoietic diseases
Heparitin Sulfate - metabolism
Heparitin Sulfate - physiology
Humans
Immunodeficiencies. Immunoglobulinopathies
Immunoglobulin gamma-Chains - genetics
Immunoglobulinopathies
Immunopathology
Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis
Medical sciences
Mice
Mice, Knockout
Multiple Myeloma - drug therapy
Multiple Myeloma - metabolism
Multiple Myeloma - pathology
N-Acetylglucosaminyltransferases - antagonists & inhibitors
N-Acetylglucosaminyltransferases - genetics
N-Acetylglucosaminyltransferases - physiology
RNA, Small Interfering - pharmacology
Syndecan-1 - genetics
Syndecan-1 - metabolism
Xenograft Model Antitumor Assays
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Summary:Expression of the heparan sulfate proteoglycan syndecan-1 is a hallmark of both normal and multiple myeloma (MM) plasma cells. Syndecan-1 could affect plasma cell fate by strengthening integrin-mediated adhesion via its core protein and/or by accommodating and presenting soluble factors via its HS side chains. Here, we show that inducible RNAi-mediated knockdown of syndecan-1 in human MM cells leads to reduced growth rates and a strong increase of apoptosis. Importantly, knockdown of EXT1, a copolymerase critical for HS chain biosynthesis, had similar effects. Using an innovative myeloma xenotransplantation model in Rag-2−/−γc−/− mice, we demonstrate that induction of EXT1 knockdown in vivo dramatically suppresses the growth of bone marrow localized myeloma. Our findings provide direct evidence that the HS chains of syndecan-1 are crucial for the growth and survival of MM cells within the bone marrow environment, and indicate the HS biosynthesis machinery as a potential treatment target in MM.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2009-02-204396