The role of PHF6 in T-cell acute lymphoblastic leukemia

项目描述（由申请人提供）：本项目旨在建立PHF6 （plant homeodomain finger 6）的作用机制，PHF6是在20%的原发性T细胞急性淋巴细胞白血病（T- ALL）样本中突变的一种新的肿瘤抑制基因。值得注意的是，PHF6基因位于X染色体上，PHF6突变几乎只在男性T-ALL患者中发现。此外，PHF6突变特征性地与TLX1和TLX3的激活相关，TLX1和TLX3是T-ALL中由染色体易位激活的两种高度相关的转录因子癌基因。此外，PHF6有两个PHD结构域参与表观遗传组蛋白标记的识别，这表明在基因表达的表观遗传调控中起作用。此外，我们的初步结果表明，PHF6定位于染色质，并与NuRD复合物和精氨酸甲基转移酶相互作用，这些酶参与了组蛋白尾部翻译后修饰的“写入”。我们的中心假设是PHF6突变可能通过破坏t细胞祖细胞中调节细胞增殖和存活的特定表观遗传机制而参与T-ALL的发病机制。此外，我们提出TLX转录因子癌基因的异常表达与T细胞转化中PHF6的突变缺失协同作用，这在T- ALL的发病机制中构成了一条独特的致癌途径。因此，本研究计划的目标是明确PHF6的分子和细胞功能，并分析该基因在TLX1诱导的T-ALL中的抑瘤活性。为此，我们将分析PHF6在表观遗传标记识别和基因表达控制中的作用，并利用基因操纵动物模型在体内测试PHF6的肿瘤抑制功能。

DESCRIPTION (provided by applicant): This project aims to establish the mechanisms of action of PHF6 (plant homeodomain finger 6), a new tumor suppressor gene mutated in 20% of primary T-cell acute lymphoblastic leukemia (T- ALL) samples. Notably, the PHF6 gene is located on chromosome X and PHF6 mutations are almost exclusively found in male patients with T-ALL. In addition PHF6 mutations are characteristically associated with activation of TLX1 and TLX3, two highly related transcription factor oncogenes activated by chromosomal translocations in T-ALL. Moreover, PHF6 has two PHD domains involved in the recognition of epigenetic histone marks, which suggests a role in the epigenetic regulation of gene expression. In addition, our preliminary results demonstrate that PHF6 localizes to the chromatin and interacts with the NuRD complex and Arginine methyl transferases implicated in the "writing" of this posttranslational modification in histone tails. Our central hypothesis is that PHF6 mutations may contribute to the pathogenesis of T-ALL by disrupting specific epigenetic mechanisms that regulate cell proliferation and survival in T-cell progenitor cells. Furthermore, we propose that the aberrant expression of TLX transcription factor oncogenes cooperates with mutational loss of PHF6 in T-cell transformation and that this constitutes a distinct oncogenic pathway in the pathogenesis of T- ALL. Thus, the goals of this research proposal are to define the molecular and cellular functions of PHF6 and to analyze the tumor suppressor activity of this gene in the context of TLX1 induced T-ALL. Towards this goal we will analyze the role of PHF6 in the recognition of epigenetic marks and the control of gene expression and test the tumor suppressor function of Phf6 in vivo using genetically manipulated animal models.