The role of PHF6 in T-cell acute lymphoblastic leukemia

描述（由申请人提供）：本项目旨在建立PHF 6（植物同源结构域指6）的作用机制，PHF 6是一种新的肿瘤抑制基因，在20%的原发性T细胞急性淋巴细胞白血病（T-ALL）样本中发生突变。值得注意的是，PHF 6基因位于X染色体上，PHF 6突变几乎仅见于T-ALL男性患者。此外，PHF 6突变与TLX 1和TLX 3的激活相关，这两种高度相关的转录因子癌基因在T-ALL中由染色体易位激活。此外，PHF 6具有两个参与识别表观遗传组蛋白标记的PHD结构域，这表明在基因表达的表观遗传调节中起作用。此外，我们的初步研究结果表明，PHF 6定位于染色质和相互作用的NuRD复合物和精氨酸甲基转移酶牵连在“写作”的这种翻译后修饰组蛋白的尾巴。我们的中心假设是PHF 6突变可能通过破坏调节T细胞祖细胞增殖和存活的特定表观遗传机制而导致T-ALL的发病。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PHF 6的突变丢失相配合，这构成了T-ALL发病机制中的独特致癌途径。因此，本研究计划的目标是确定PHF 6的分子和细胞功能，并分析该基因在TLX 1诱导的T-ALL背景下的肿瘤抑制活性。为了实现这一目标，我们将分析PHF 6在识别表观遗传标记和控制基因表达中的作用，并使用遗传操作的动物模型在体内测试PHF 6的肿瘤抑制功能。 公共卫生相关性：本项目旨在分析PHF 6基因在T细胞急性淋巴细胞白血病（T-ALL）发病机制中的肿瘤抑制作用，使用生物化学和遗传学方法相结合。阐明PHF 6的分子功能以及在这种染色质相关因子突变丢失后介导T细胞转化的机制可能会为合理开发针对T-ALL的新疗法发现新靶点。

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. PUBLIC HEALTH RELEVANCE: This project aims to analyze the tumor suppressor role of the PHF6 gene in the pathogenesis of T-cell acute lymphoblastic leukemias (T-ALL) using a combination of biochemical and genetic approaches. Elucidation of the molecular functions of PHF6 and the mechanisms that mediate T-cell transformation upon mutational loss of this chromatin associated factor may uncover new targets for the rational development of new therapies against T-ALL.