PHF6突变在急性T淋巴细胞白血病中作用机制研究

急性T淋巴细胞白血病（T-ALL）是T前体细胞恶性转化引起的侵袭性血液肿瘤，这一恶变过程是由多种异常信号通路共同参与的复杂进程。PHF6是表观遗传学高频突变基因，研究证实其作为起始驱动突变或伴随突变在T前体细胞恶性转化过程中具有重要作用，但其多途径参与T细胞恶性演变的分子机制尚不明确。我们发现PHF6(R274*)在T-ALL男性患者中具有较高的突变频率，PHF6缺失性突变协同JAK3突变促进T-ALL疾病进程。本项目拟在此研究基础上，应用多组学技术，在Phf6(R274*/Y)条件敲入小鼠和Phf6(-/Y)条件敲除小鼠模型中确定PHF6突变调控T-ALL发生和发展的作用机制，探索其信号通路中的关键分子在T-ALL的靶向治疗中的作用。本项目预期通过临床疾病和动物模型研究，解析T淋巴细胞白血病的关键机制，为临床靶向干预策略提供科学依据。

T-ALL is an aggressive hematological tumor caused by the malignant transformation of T precursor cells. This complex process involves multiple abnormal signaling pathways. PHF6 is an epigenetic gene with high frequency of gene mutations in leukemia. It has been shown that as either initial driving mutation or accompanied mutation, PHF6 mutation plays an important role in T cell malignant transformation, although the molecular mechanism of how PHF6 participates in the malignant evolution of T cells is still unclear. PHF6(R274*) mutation has a higher frequency in T-ALL male patients. Interestingly, we found that PHF6 mutation and JAK3 mutation cooperate in leukemia development. Based on these findings, we here propose to use multi-omics analysis, and Phf6(R274*/Y) conditional knock-in and Phf6(-/Y) conditional knockout mouse models to study the role and the mechanism of PHF6 in regulating T-ALL initiation and development. We will also explore the key molecule targets in PHF6 signaling pathway that can be potentially used for T-ALL treatment. We expect by finishing these clinical case and animal model studies, we will delineate the key mechanism of T-ALL initiation and development, and thus provide scientific bases for targeted clinical intervention for T-ALL.