抑癌基因MLL2对细胞分裂的调控及抑癌机理

MLL2 is a new, potential tumor suppressor found to be deficient in significant portions of many types of human cancers. A small number of studies have been done to describe MLL2’s biochemical properties as a histone methytransferase. However, MLL2’s full range of functions and how MLL2 deficiency contributes to cancer remains to be further explored. Interestingly, our acquired data suggest that in normal, untransformed cells, MLL2 is localized primarily in cytoplasm, suggesting that it may have functions besides epigenetic regulation. Moreover, MLL2 is localized to mitotic spindle and midbody during cell division, and suppression of MLL2 causes mitotic defects and uneven chromosome distribution during mitosis. It suggests that MLL2 deficiency may contribute to tumorigenesis through aneuploidy, and MLL2 deficient cancer cells may respond differently to anti-mitosis chemodrugs such as taxol and vincristine. Based on this, we will further investigate the role MLL2 played in cytoplasm and its function during mitosis. We will also utilize MLL2 knockout and RNAi mice to study whether and how MLL2 deficiency contributes to tumor formation and maintenance. Knowledge gained from this study will help shed light on MLL2’s function, in particular its function independent of epigenetic regulations. It will also help us understand how MLL2 deficiency could help tumor formation as well as the molecular properties of MLL2-deficient tumors.

MLL2是近期发现的，在许多类型的肿瘤中高频失活突变的基因。目前有少量文献报道了MLL2作为组蛋白甲基转移酶的生化机理，但是MLL2的生物学功能和MLL2失活与肿瘤的关系仍有待深入研究。我们前期研究发现，在正常组织分裂间期的细胞里，MLL2主要位于细胞质，提示MLL2在正常细胞中可能有表观遗传调控以外的功能。我们还发现，在有丝分裂过程中，MLL2定位于纺锤体和中间体，并且MLL2的敲减会干扰有丝分裂和染色体在子代细胞中的分配。这提示MLL2失活可能通过诱导染色体非整倍性来推动肿瘤细胞进化，而MLL2失活的肿瘤细胞可能对紫杉醇等化疗药物有不同的应答。我们将深入研究MLL2在细胞质中的生物学功能和它在有丝分裂中的作用。我们还将利用MLL2敲除和RNAi小鼠，研究MLL2的失活对肿瘤的形成和维持的意义。这将帮助我们更好地认识MLL2这一重要基因的功能、它的抑癌机理以及MLL2失活的肿瘤的特性。

MLL2是一个在许多类型的肿瘤里发生广泛失活突变的新型抑癌基因，本项目聚焦于MLL2的失活对肿瘤发生发展和治疗效果的影响。我们发现，1）MLL2在细胞有丝分裂过程中起一定的调控作用，其缺失导致细胞有丝分裂的紊乱，这可能可以解释MLL2失活为何促进肿瘤发生；2）通过RNAi技术全身敲减MLL2后，我们意外地发现小鼠迅速变胖，提示MLL2在代谢调控中的重要作用。由于小鼠迅速发胖，我们技术上无法继续有效研究MLL2的失活是否促进肿瘤发生，因此继续研究了MLL2在脂肪代谢中的作用，发现MLL2对于Hedgehog信号通路的调控作用；3）针对MLL2失活的肿瘤，我们研究了MLL2的失活如何影响肿瘤药物对癌细胞的杀伤，为MLL2失活的肿瘤的精准治疗提出了潜在探索方向；4）MLL2与另一个抑癌基因UTX组成一个蛋白复合体，我们用组织特异性敲除的小鼠模型，证实了UTX在淋巴瘤中的抑癌作用，及其对于人类男女癌症发病率差异的潜在贡献。我们也系统性阐述了UTX失活对于抗癌药物敏感性的影响，发现UTX失活与MLL2失活对于药物敏感性的影响有显著差异。这提示虽然MLL2和UTX作为一个蛋白复合体发挥作用，它们在肿瘤发生和肿瘤药物应答过程中的功能可能有所分化。这有助于我们理解MLL2/UTX复合物中不同突变对肿瘤诊疗的意义。