mTORC2通过分子伴侣介导的自噬促进多发性骨髓瘤生长与耐药的机制研究

多发性骨髓瘤(MM)是不可治愈的恶性疾病，几乎所有的患者最终将面临耐药、复发等瓶颈。我们前期研究发现：mTORC2/AKT能促进前B细胞白血病及MM细胞的耐药及凋亡受阻。但mTORC2/AKT在上述病理生理过程中的作用机制尚不清楚。最新研究发现：mTORC2调控的分子伴侣介导的自噬（CMA）对多种实体肿瘤的生长、凋亡和耐药发挥重要作用，但其在MM疾病进程中的作用研究甚少。我们的预实验发现：对mTORC2/AKT的抑制能显著增加MM细胞中自噬微管相关蛋白轻链3β(LC3β)的表达。鉴于LC3β是CMA中的重要调控元件，我们提出以下科学设想：mTORC2/AKT可能通过CMA途径促进MM细胞的生长与耐药。围绕上述科学设想，我们拟采用生物化学及分子生物学手段深入探索mTORC2在多发性骨髓瘤分子伴侣介导自噬中的作用及其机制，从而为MM的诊治提供新的思路。

Multiple myeloma (MM) is a kind of incurable malignant diseases at present. Almost the patients will eventually face the resistance and relapse bottlenecks. On the early stage of our team, we found that mTORC2/AKT signaling pathway in pre-B cell leukemia and multiple myeloma can significantly promote the chemoresistance of tumor cells and the apoptosis of tumor cells restrained（Blood,2012,119:6080-6088.Biomed Res Int,2014:p.190629.） But the role of mTORC2/AKT in the pathophysiological process mechanism is unclear. A new study has found that: mTORC2 directed the chaperone mediated autophagy (CMA) plays an important role in the growth, apoptosis and chemoresistance of a variety of solid tumors, but these researches on multiple myeloma are less . Our preliminary experiment found that suppression of mTORC2/AKT signal pathway could significantly increase the expression of MM cell autophagy microtubule associated protein light chain 3 beta (LC3 beta). Given the LC3 beta is an important regulatory elements in CMA, we put forward the following scientific idea: mTORC2/AKT signaling pathways may be affected by CMA to promote MM cells growth and resistance. Around the scientific idea, this research will explore the mechanism of mTORC2 mediated CMA in multiple myeloma, intending to adopt the methods of biochemistry and molecular biology. Thus it will provide a new method for the diagnosis and treatment of multiple myeloma.