Plant homeodomain finger protein 6 in the regulation of normal and malignant hematopoiesis.
Plant homeodomain finger protein 6 in the regulation of normal and malignant hematopoiesis.
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DOI：
10.1097/moh.0000000000000588
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发表时间：
2020-05
影响因子：
3.2
通讯作者：
S. Miyagi;A. Iwama
中科院分区：
文献类型：
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作者：
S. Miyagi;A. Iwama
尽管越来越多的关于白血病基因组的测序数据已经强调了植物同源结构域指蛋白6（PHF 6）的肿瘤抑制功能，但直到最近，它在造血系统中的作用仍然难以捉摸。本文就PHF6基因敲除小鼠模型的研究进展，对PHF6在正常造血和白血病发生中的作用进行综述。在小鼠模型中，Phf 6的缺失增强了造血干细胞（HSC）在连续移植过程中的骨髓重建能力，而造血系统中缺乏Phf 6表达的供体小鼠在稳态下没有表现出任何明显的表型。Phf 6激活肿瘤坏死因子α（TNFα）通路中的效应子。因此，Phf 6缺陷减弱效应子的表达，并赋予对TNFα介导的HSC生长抑制的抗性。此外，Phf6的缺失促进了由异常TLX3表达或活性NOTCH突变诱导的白血病的发展。Phf 6通过调控TNFα途径限制HSC的自我更新。phf 6具有肿瘤抑制功能，其缺失与白血病病变协同作用，促进血液系统恶性肿瘤的发生。
PURPOSE OF REVIEW Even though an increasing amount of sequencing data on the leukemia genome has highlighted a tumor-suppressive function for plant homeodomain finger protein 6 (PHF6), its role in the hematopoietic system remained elusive until recently. The purpose of this review is to describe the role of PHF6 in normal hematopoiesis and leukemogenesis based on recent findings from knockout mouse models. RECENT FINDINGS In a mouse model, the loss of Phf6 enhanced the bone marrow repopulating capacity of hematopoietic stem cells (HSCs) during serial transplantations without transforming hematopoietic cells, whereas donor mice, which lacked Phf6 expression in the hematopoietic system, did not show any apparent phenotypes in the steady-state. Mechanistically, Phf6 activates effectors in the tumor necrosis factor α (Tnfα) pathway. Therefore, a Phf6 deficiency attenuates the expression of the effectors and confers resistance against Tnfα-mediated growth inhibition to HSCs. Moreover, the loss of Phf6 promoted the development of leukemia induced by aberrant TLX3 expression or an active NOTCH mutation. SUMMARY Phf6 restricts the self-renewal of HSCs by governing the Tnfα pathway. Phf6 fulfills a tumor-suppressive function, and its loss synergizes with leukemic lesions to promote the onset of hematological malignancies.