Reelin在多发性骨髓瘤的表达及其在疾病进展中的作用

Reelin is an extracellular matrix glycoprotein that plays a pivotal role in the regulation of cell migration and positioning control. Little is known of the role of reelin in multiple myeloma. We found expression of reelin in primary myeloma cells and cell lines. The expression level is negatively correlated with the progress-free survival and overall survival of the patients. Mice with natural deficiency in reelin had less pre-B and immature B cells. Compared to those from wild type, the reelin-deficient B cell populations undergo more apoptosis in vitro. Thus, we hypothesize that reelin may play an important role in promoting the survival and adhesion of myeloma cells in the microenvironment. We will increase the numbers of patients to confirm the relationship between reelin expression and the progression of multiple myeloma. We will also explore the regulation of reelin expression in myeloma cells. The results from this research will facilitate our understanding of the development and progression of myeloma and the role of the bone marrow microenvironment on myeloma cells. It will also provide new clues and evidence for better diagnosis and prognosis, and more therapeutic potentials.

前期我们发现调节神经元迁移、稳定细胞骨架的关键分子reelin在多发性骨髓瘤细胞系和患者细胞中表达，表达水平与生存呈显著负相关。动物实验示，与野生型相比，reelin天然缺陷小鼠的pre-B和immature B细胞数量减少，体外存活能力下降。我们推测reelin可能影响骨髓瘤细胞在骨髓微环境中的粘附和存活，从而导致疾病进展。本项目将通过如下几个方面的验证：1）进一步明确reelin表达水平与骨髓瘤预后的关系；2）探讨reelin在骨髓瘤细胞的表达调控机制。上述研究的结果将促进对骨髓瘤发生和发展机理的深入理解，不仅具有重大理论意义，并有望为reelin表达异常的骨髓瘤患者提供医学干预的新思路。

通过临床以及实验室研究，我们发现在临床上Reelin与MM患者生存负相关，实验室上我们发现Reelin能够促进多发性骨髓瘤细胞对纤维连接蛋白的粘附。reelin过表达能够促进MM细胞对纤维连接蛋白（fibronectin, FN）和骨髓基质细胞系的粘附，reelin特异性siRNA能够抑制MM细胞的粘附，而外源给予reelin重组蛋白不仅促进MM细胞的粘附，还能减缓reelin siRNA的粘附抑制作用，Reelin中和抗体CR50能够抑制reelin过表达导致的促粘附作用。重组蛋白的这一作用在洗脱后仍然存在，提示reelin的促粘附作用可能是间接通过改变其它分子实现的。另外，虽然reelin也是细胞外基质蛋白，但MM细胞不能对其产生粘附。在机制上我们首次发现在MM细胞中，reelin是通过活化整合素β1以及其信号通路，活化Akt和Stat3来完成其对骨髓瘤细胞的促粘附和促存活作用。另外，在整合素β1通路能够活化Stat3方面，我们的研究也处于国际领先地位。已经发表SCI三篇，中文核心期刊5篇，专利申请1个，正在审稿SCI文章3篇。