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

Blood. 2010 Jan 21;115(3):601-4. doi: 10.1182/blood-2009-02-204396. Epub 2009 Nov 13.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • DNA-Binding Proteins / genetics
  • Doxycycline / administration & dosage
  • Drug Delivery Systems
  • Gene Targeting
  • Heparitin Sulfate / metabolism
  • Heparitin Sulfate / physiology*
  • Humans
  • Immunoglobulin gamma-Chains / genetics
  • 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

Substances

  • DNA-Binding Proteins
  • Immunoglobulin gamma-Chains
  • RNA, Small Interfering
  • Rag2 protein, mouse
  • Sdc1 protein, mouse
  • Syndecan-1
  • Heparitin Sulfate
  • N-Acetylglucosaminyltransferases
  • exostosin-1
  • Doxycycline