Phf6 Loss Enhances HSC Self-Renewal Driving Tumor Initiation and Leukemia Stem Cell Activity in T-ALL
Phf6 Loss Enhances HSC Self-Renewal Driving Tumor Initiation and Leukemia Stem Cell Activity in T-ALL
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DOI：
10.1158/2159-8290.cd-18-1005
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发表时间：
2019-03-01
期刊：
影响因子：
28.2
通讯作者：
Ferrando, Adolfo A.
中科院分区：
文献类型：
--
作者：
Wendorff, Agnieszka A.;Quinn, S. Aidan;Ferrando, Adolfo A.
植物同源结构域6基因（PHF6）在人t细胞急性淋巴细胞白血病（T-ALL）中经常发生突变；然而，它在白血病发展中的具体功能作用仍有待确定。在这里，我们发现PHF6的缺失是白血病转化的早期突变事件。从机制上讲，造血系统中Phf6的基因失活通过使Phf6敲除的造血干细胞更安静，更不容易受到应激诱导的激活，从而增强了造血干细胞（HSC）在化疗后的长期自我更新和造血恢复。与白血病启动肿瘤抑制作用一致，造血祖细胞中Phf6的失活降低了notch1诱导的T-ALL发展的阈值。此外，白血病淋巴细胞中Phf6的缺失激活了白血病干细胞转录程序，并驱动T-ALL白血病启动细胞活性增强。这些结果暗示Phf6在控制HSC稳态和长期自我更新中起作用，并支持Phf6丢失作为T-ALL中白血病启动细胞活性的驱动因素。意义：Phf6控制HSC稳态、白血病起始和T-ALL白血病起始细胞自我更新。这些结果证实了PHF6突变在T-ALL发病机制中作为白血病干细胞活性的早期事件和驱动因素的作用。
The plant homeodomain 6 gene (PHF6) is frequently mutated in human T-cell acute lymphoblastic leukemia (T-ALL); however, its specific functional role in leukemia development remains to be established. Here, we show that loss of PHF6 is an early mutational event in leukemia transformation. Mechanistically, genetic inactivation of Phf6 in the hematopoietic system enhances hematopoietic stem cell (HSC) long-term self-renewal and hematopoietic recovery after chemotherapy by rendering Phf6 knockout HSCs more quiescent and less prone to stress-induced activation. Consistent with a leukemia-initiating tumor suppressor role, inactivation of Phf6 in hematopoietic progenitors lowers the threshold for the development of NOTCH1-induced T-ALL. Moreover, loss of Phf6 in leukemia lymphoblasts activates a leukemia stem cell transcriptional program and drives enhanced T-ALL leukemia-initiating cell activity. These results implicate Phf6 in the control of HSC homeostasis and long-term self-renewal and support a role for PHF6 loss as a driver of leukemia-initiating cell activity in T-ALL.SIGNIFICANCE: Phf6 controls HSC homeostasis, leukemia initiation, and T-ALL leukemia-initiating cell self-renewal. These results substantiate a role for PHF6 mutations as early events and drivers of leukemia stem cell activity in the pathogenesis of T-ALL.