The cellular senescence of leukemia-initiating cells from acute lymphoblastic leukemia is postponed by β-Arrestin1 binding with P300-Sp1 to regulate hTERT transcription.
The cellular senescence of leukemia-initiating cells from acute lymphoblastic leukemia is postponed by β-Arrestin1 binding with P300-Sp1 to regulate hTERT transcription.
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β-Arrestin1 与 P300-Sp1 结合调节 hTERT 转录可推迟急性淋巴细胞白血病白血病起始细胞的细胞衰老
DOI：
10.1038/cddis.2017.164
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发表时间：
2017-04-20
影响因子：
9
通讯作者：
Zou L
中科院分区：
文献类型：
--
作者：
Liu S;Liu H;Qin R;Shu Y;Liu Z;Zhang P;Duan C;Hong D;Yu J;Zou L
虽然我们以前报道过B系急性淋巴细胞白血病（B-ALL LICs）的白血病起始细胞的自我更新受多功能蛋白β-Arrestin 1的调控，但细胞衰老对LICs的命运和白血病的进展至关重要，值得进一步研究。我们发现β-Arrestin 1的缺失延长了B-ALL LIC的群体倍增时间和衰老细胞的百分比，这是细胞衰老的标志。此外，β-Arrestin 1的缺乏增强了白血病Reh细胞和B-ALL-LCs衍生白血病小鼠中与衰老相关的蛋白质（CBX、HIRA）和基因（P53、P16）的表达。进一步的研究结果表明，β-Arrestin 1的缺失通过介导hTERT-端粒酶-端粒轴诱导Reh细胞衰老，端粒酶活性抑制剂BIBR 1532可逆转β-Arrestin 1的失活。重要的是，β-Arrestin 1的缺失降低了Sp1与hTERT启动子在−28至−36 bp区域的结合。该关键区域的反义寡核苷酸下调了hTERT的转录，加重了Reh细胞的衰老。进一步的研究表明，缺失β-Arrestin 1后，P300与Sp1的相互作用减弱，从而使Sp1与hTERT启动子的结合减弱，hTERT转录下调，端粒酶活性降低，端粒长度缩短，促进Reh细胞衰老。有趣的是，B-ALL LIC中老年细胞的百分比减少，这与儿童B-ALL患者的良好预后和β-Arrestin 1 mRNA表达呈负相关。我们的研究揭示了B-ALL LIC的衰老受β-Arrestin 1调控，为hTERT启动子关键区域促进细胞衰老提供了潜在的白血病治疗靶点。
Although we previously reported that the self-renewal of leukemia-initiating cells of B-lineage acute lymphoblastic leukemia (B-ALL LICs) was regulated by β-Arrestin1, a multiple-function protein, the cellular senescence is critical for LICs fate and leukemia progress, and worthy for further investigation. Here we found that depletion of β-Arrestin1 extended the population doubling time and the percentage of senile cells, the signatures of cellular senescence, of B-ALL LICs. Moreover, lack of β-Arrestin1 enhanced the expression of proteins (CBX, HIRA) and genes (P53, P16) related to senescence in leukemic Reh cells and B-ALL-LICs-derived leukemic mice. Further results showed that loss of β-Arrestin1 induced senescence of Reh cells through mediating hTERT-telomerase-telomere axis, which was reversed by BIBR1532, the telomerase activity inhibitor. Importantly, depletion of β-Arrestin1 decreased the binding of Sp1 to hTERT promoter at the region of −28 to −36 bp. The anti-sense oligonucleotide of this key region downregulated the transcription of hTERT and aggravated the senescence of Reh cells. Further data demonstrated that the depleted β-Arrestin1 reduced the interaction of P300 with Sp1, thus to reduce Sp1 binding to hTERT promoter, downregulate hTERT transcription, decrease telomerase activity, shorten telomere length, and promote Reh cell senescence. Interestingly, the percentage of senile cells in B-ALL LICs was decreased, which was negatively correlated to good prognosis and β-Arrestin1 mRNA expression in childhood B-ALL patients. Our study shed a light on the senescence of B-ALL LICs and is regulated by β-Arrestin1, providing the potential therapeutic target of leukemia by promoting cellular senescence with a key region of hTERT promoter.
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