MLL白血病是一种常见的急性白血病，预后极差，目前临床上尚无有效治疗手段，亟待开发新型治疗策略。MLL融合基因作为MLL白血病的驱动因素，与多数癌基因相似，除了肿瘤促进活性外,还拥有内在肿瘤抑制活性，表现为过表达时抑制肿瘤生长。我们在多年从事MLL白血病发病机制研究的基础上，发现蛋白酶体抑制剂可以促进MLL融合蛋白在白血病细胞内的进一步积累，使得内在肿瘤抑制活性成为其主要功能，从而特异的杀死MLL白血病细胞，达到靶向治疗的目的。这说明利用MLL融合基因的内在肿瘤抑制活性进行MLL白血病的靶向治疗在理论和实践上是可行的。有趣的是，只有表现为B-ALL而非AML的MLL白血病细胞，才对蛋白酶体抑制剂高度敏感。本项目将对蛋白酶体抑制剂特异地在B-ALL的MLL白血病细胞中诱发内在肿瘤抑制活性，产生细胞毒性的分子机制进行深入研究，并且对该新型靶向治疗策略进行临床前研究，为其临床转化应用打下基础。

Leukemias with MLL translocation portend poor prognosis and are commonly refractory to conventional chemotherapies. Like many of the known oncogenes, MLL fusions also possess the intrinsic tumor suppression activity. Appropriate levels of MLL-fusions are required to induce leukemia, whereas their overexpression appears detrimental to cells. We found leukemogenic MLL-fusions could be induced through pharmacological means, compromising MLL leukemia cells and conferring in vitro preclinical benefits. Interestingly, only precursor-B lymphoid but not myeloid MLL leukemia cells are exquisitely sensitive to bortezomib, a proteasome inhibitor utilized in clinics, exhibiting a highly cell-type, oncogene specific manners. Hence, it is plausible to exploit inherent tumor-suppressor properties of individual oncogenic fusions to treat specific cancers. In this proposed proposal, we will determine the underlying mechanistic basis and demonstrating the in vivo preclinical feasibility in selective killing of precursor-B lymphoid MLL leukemia cells by disrupting the MLL-AF4 homeostasis with proteasome inhibitors. Our study will offer a proof-of-principle clinical prototype that turns oncogenic fusions into intrinsic suicidal machinery.