去泛素化酶USP5调控P53通路在伴E2A-PBX1成人ALL的致病机制研究

The (1;19)(q23;p13) translocation，which results in the production of the E2A-PBX1 fusion protein, is associated with poor outcome in adult acute lymphoblastic leukemia (ALL). However, mechanisms driving disease progression are unknown. We summarized clinical and molecular characteristics of adult ALL with E2A-PBX1 in our institute. High-throughput sequencing identified that 22% patients had functional mutations in the deubiquitinating enzyme USP5. Our institute has reported that ubiquitination pathway played a role in the mechanisms of ALL with E2A-PBX1.And we have already found that the expression of USP5 mRNA in E2A-PBX1 positive leukemia cell lines was increased, while p53 mRNA expression was decreased. So it is plausible that USP5 may regulate P53 pathway to block apoptosis and promote malignant transformation in ALL with E2A-PBX1. To test these hypotheses, we summarize more samples, analyze the relationship between USP5 mutation and prognosis, test the gene expression profile and signal pathways in patient samples. Then we knock down or overexpress USP5 to detect gene expression and malignant transformation in vitro and in vivo. We also detect the effect and mechanism of USP5 in the stabilization of E2A-PBX1.The efficiency of target therapy is also tested in PDX model. This study will provide theoretical basis for elucidating the pathogenesis and seeking new therapeutic targets of adult ALL with E2A-PBX1.

t(1;19)(q23;p13)易位形成E2A-PBX1蛋白，伴有该遗传学异常的成人急性淋巴细胞白血病（ALL）预后恶劣，但机制未明。我们总结了本单位E2A-PBX1阳性成人ALL临床及分子学特征，高通量测序结果发现22%患者存在去泛素化酶USP5功能区突变。本单位前期研究已证实泛素化途径在这类白血病发病中发挥了作用。此外进一步验证，我们发现E2A-PBX1阳性白血病细胞系中USP5及P53表达量降低。故提出假说，USP5通过P53通路抑制细胞凋亡，促进恶性转化，导致疾病发生。为验证假说，我们将进一步扩大样本，分析USP5突变与预后关系，检测患者泛素化相关基因表达谱及重要信号通路分子表达；通过敲除或过表达USP5，在体内、体外观察恶性转化、基因表达、USP5对E2A-PBX1蛋白稳定性的影响；构建PDX模型，验证靶向药物疗效。为阐明伴E2A-PBX1的ALL发病机制、寻找治疗靶点提供依据。

t(1;19)(q23;p13)易位形成E2A-PBX1蛋白，伴有该遗传学异常的成人急性淋巴细胞白血病（ALL）预后恶劣，但其机制未明。我们总结了大量E2A-PBX1阳性ALL成人及儿童患者的临床特征，并对该群体进行了遗传学分析，描述其基因组图谱，探讨该亚型ALL的发病机制。我们发现，伴E2A-PBX1融合基因的B-ALL是一种较罕见的白血病亚型，年龄和诱导化疗后的MRD水平是该类患者的独立危险因素，年龄越大预后越差。而异基因造血干细胞移植（HSCT），尤其是单倍体HSCT，可以改善青少年/成人患者的预后。在此类白血病患者中，常可见PBX1、PAX5、CTCF和SETD2的突变、AKT3的扩增和CDKN2A/B的缺失，青少年/成人和儿童的细胞周期、NGF信号通路和TP53转录调节的转录组存在差异。前期研究我们发现USP5可能参与了E2A-PBX1阳性B-ALL的发病机制。通过体外研究发现，USP5可能通过促进肿瘤增殖、减少凋亡、下调包括P53在内的凋亡相关蛋白、延长E2A-PBX1蛋白半衰期、稳定融合蛋白等参与了伴E2A-PBX1的B-ALL发病机制。本研究为阐明伴E2A-PBX1的ALL发病机制、寻找治疗靶点提供依据。

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