Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands.
Blood. 2010 Jan 21;115(3):601-4. doi: 10.1182/blood-2009-02-204396. Epub 2009 Nov 13.
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.
硫酸乙酰肝素蛋白聚糖 syndecan-1 的表达是正常浆细胞和多发性骨髓瘤（MM）浆细胞的一个标志。 syndecan-1 可以通过其核心蛋白增强整合素介导的黏附作用，或者通过其 HS 侧链容纳和呈现可溶性因子，从而影响浆细胞的命运。在这里，我们表明，在人 MM 细胞中诱导 RNAi 介导的 syndecan-1 敲低会导致生长速度降低和凋亡明显增加。重要的是，EXT1 的敲低，一种对于 HS 链生物合成至关重要的聚合酶，也有类似的效果。利用 Rag-2(-/-)gamma(c)(-/-)小鼠中的创新骨髓瘤异种移植模型，我们证明了体内诱导 EXT1 敲低可显著抑制骨髓中骨髓瘤的生长。我们的研究结果提供了直接证据，表明 syndecan-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 生物合成机制是 MM 的一个潜在治疗靶点。
