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 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(-/-)gamma(c)(-/-) 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.
Reijmers
Rogier M
RM
Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands.
Groen
Richard W J
RW
Rozemuller
Henk
H
Kuil
Annemieke
A
de Haan-Kramer
Anneke
A
Csikós
Tamás
T
Martens
Anton C M
AC
Spaargaren
Marcel
M
Pals
Steven T
ST
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000235:genetics; D004318:Doxycycline / Q000008:administration & dosage; D016503:Drug Delivery Systems; D018390:Gene Targeting; D006497:Heparan Sulfate / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007142:Immunoglobulin gamma-Chains / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D017351:N-Acetylglucosaminyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology*; D053668:Syndecan-1 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000099058:Exostosin 1
D004268:DNA-Binding Proteins; D004318:Doxycycline; D006497:Heparan Sulfate; D007142:Immunoglobulin gamma-Chains; D017351:N-Acetylglucosaminyltransferases; D034741:RNA, Small Interfering; D053668:Syndecan-1; D000099058:Exostosin 1; C499308:Rag2 protein, mouse; C508242:Sdc1 protein, mouse