Lan Yanjie, Yuan Shengnan, Guo Tengxiao, Hou Shuaibing, Zhao Fei, Yang Wanzhu, Cao Yigeng, Chu Yajing, Jiang Erlie, Yuan Weiping, Wang Xiaomin
State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300020, China.
Tianjin Institutes of Health Science, Tianjin 301600, China.
iScience. 2023 May 5;26(6):106817. doi: 10.1016/j.isci.2023.106817. eCollection 2023 Jun 16.
The PHD finger protein 6 (PHF6) mutations frequently occurred in hematopoietic malignancies. Although the R274X mutation in PHF6 ) is one of the most common mutations identified in T cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML) patients, the specific role of in hematopoiesis remains unexplored. Here, we engineered a knock-in mouse line with conditional expression of Phf6-mutated protein in the hematopoietic system ( mouse). The mice displayed an enlargement of hematopoietic stem cells (HSCs) compartment and increased proportion of T cells in bone marrow. More T cells were in activated status than control. Moreover, mutation led to enhanced self-renewal and biased T cells differentiation of HSCs as assessed by competitive transplantation assays. RNA-sequencing analysis confirmed that mutation altered the expression of key genes involved in HSC self-renewal and T cell activation. Our study demonstrated that plays a critical role in fine-tuning T cells and HSC homeostasis.
PHD指蛋白6（PHF6）突变在造血系统恶性肿瘤中频繁发生。尽管PHF6中的R274X突变是在T细胞急性淋巴细胞白血病（T-ALL）和急性髓系白血病（AML）患者中发现的最常见突变之一，但其在造血过程中的具体作用仍未得到探索。在此，我们构建了一种在造血系统中条件性表达Phf6突变蛋白的基因敲入小鼠品系（Phf6R274X小鼠）。Phf6R274X小鼠表现出造血干细胞（HSC）区室扩大以及骨髓中T细胞比例增加。与对照相比，更多的Phf6R274X T细胞处于活化状态。此外，通过竞争性移植试验评估，Phf6R274X突变导致HSC的自我更新增强以及T细胞分化偏向。RNA测序分析证实，Phf6R274X突变改变了参与HSC自我更新和T细胞活化的关键基因的表达。我们的研究表明，Phf6在微调T细胞和HSC稳态中起关键作用。
