Targeting EXT1 reveals a crucial role for heparan sulfate in the growth of multiple myeloma
Targeting EXT1 reveals a crucial role for heparan sulfate in the growth of multiple myeloma
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DOI：
10.1182/blood-2009-02-204396
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发表时间：
2010-01-21
期刊：
影响因子：
20.3
通讯作者：
Pals, Steven T.
中科院分区：
文献类型：
--
作者：
Reijmers, Rogier M.;Groen, Richard W. J.;Pals, Steven T.
硫酸乙酰肝素蛋白聚糖syndecan-1的表达是正常和多发性骨髓瘤（MM）浆细胞的标志。Syndecan-1可以通过其核心蛋白增强整合素介导的粘附和/或通过其HS侧链容纳和呈递可溶性因子来影响浆细胞的命运。在这里，我们表明，在人MM细胞中，诱导型RNAi介导的syndecan-1敲低导致生长速率降低和凋亡的强烈增加。重要的是，敲低对HS链生物合成至关重要的共聚酶EXT 1具有类似的效果。在Rag-2（-/-）gamma（-/-）（c）小鼠中使用创新的骨髓瘤异种移植模型，我们证明了体内EXT 1敲低的诱导显著抑制了骨髓局部骨髓瘤的生长。我们的发现提供了直接证据，证明多配体蛋白聚糖-1的HS链对于骨髓环境中MM细胞的生长和存活至关重要，并表明HS生物合成机制作为MM中的潜在治疗靶标。2010; 115：601-604）
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 integrinmediated 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. (Blood. 2010; 115: 601-604)