JZUS - Journal of Zhejiang University SCIENCE

Journal of Zhejiang University SCIENCE B

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Genome-wide CRISPR screening identifies critical role of phosphatase and tensin homologous (PTEN) in sensitivity of acute myeloid leukemia to chemotherapy

Author(s): Liming LIN, Jingjing TAO, Ying MENG, Yichao GAN, Xin HE, Shu LI, Jiawei ZHANG, Feiqiong GAO, Dijia XIN, Luyao WANG, Yili FAN, Boxiao CHEN, Zhimin LU, Yang XU
Affiliation(s): Department of Hematology, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, China; more
Corresponding email(s): zhiminlu@zju.edu.cn, yxu@zju.edu.cn
Key Words: Genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) library; Phosphatase and tensin homologous (PTEN); Rapamycin; Acute myeloid leukemia (AML); Chemotherapy

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Liming LIN, Jingjing TAO, Ying MENG, Yichao GAN, Xin HE, Shu LI, Jiawei ZHANG, Feiqiong GAO, Dijia XIN, Luyao WANG, Yili FAN, Boxiao CHEN, Zhimin LU, Yang XU. Genome-wide CRISPR screening identifies critical role of phosphatase and tensin homologous (PTEN) in sensitivity of acute myeloid leukemia to chemotherapy[J]. Journal of Zhejiang University Science B,in press.Frontiers of Information Technology & Electronic Engineering,in press.https://doi.org/10.1631/jzus.B2300555

@article{title="Genome-wide CRISPR screening identifies critical role of phosphatase and tensin homologous (PTEN) in sensitivity of acute myeloid leukemia to chemotherapy",
author="Liming LIN, Jingjing TAO, Ying MENG, Yichao GAN, Xin HE, Shu LI, Jiawei ZHANG, Feiqiong GAO, Dijia XIN, Luyao WANG, Yili FAN, Boxiao CHEN, Zhimin LU, Yang XU",
journal="Journal of Zhejiang University Science B",
year="in press",
publisher="Zhejiang University Press & Springer",
doi="https://doi.org/10.1631/jzus.B2300555"
}

%0 Journal Article
%T Genome-wide CRISPR screening identifies critical role of phosphatase and tensin homologous (PTEN) in sensitivity of acute myeloid leukemia to chemotherapy
%A Liming LIN
%A Jingjing TAO
%A Ying MENG
%A Yichao GAN
%A Xin HE
%A Shu LI
%A Jiawei ZHANG
%A Feiqiong GAO
%A Dijia XIN
%A Luyao WANG
%A Yili FAN
%A Boxiao CHEN
%A Zhimin LU
%A Yang XU
%J Journal of Zhejiang University SCIENCE B
%P 700-710
%@ 1673-1581
%D in press
%I Zhejiang University Press & Springer
doi="https://doi.org/10.1631/jzus.B2300555"

TY - JOUR
T1 - Genome-wide CRISPR screening identifies critical role of phosphatase and tensin homologous (PTEN) in sensitivity of acute myeloid leukemia to chemotherapy
A1 - Liming LIN
A1 - Jingjing TAO
A1 - Ying MENG
A1 - Yichao GAN
A1 - Xin HE
A1 - Shu LI
A1 - Jiawei ZHANG
A1 - Feiqiong GAO
A1 - Dijia XIN
A1 - Luyao WANG
A1 - Yili FAN
A1 - Boxiao CHEN
A1 - Zhimin LU
A1 - Yang XU
J0 - Journal of Zhejiang University Science B
SP - 700
EP - 710
%@ 1673-1581
Y1 - in press
PB - Zhejiang University Press & Springer
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doi="https://doi.org/10.1631/jzus.B2300555"

Abstract
Chinese Summary
Academic Network
Reviewer Comment

Abstract: Although significant progress has been made in the development of novel targeted drugs for the treatment of acute myeloid leukemia (AML) in recent years, chemotherapy still remains the mainstay of treatment and the overall survival is poor in most patients. Here, we demonstrated the antileukemia activity of a novel small molecular compound NL101, which is formed through the modification on bendamustine with a suberanilohydroxamic acid (SAHA) radical. NL101 suppresses the proliferation of myeloid malignancy cells and primary AML cells. It induces DNA damage and caspase 3-mediated apoptosis. A genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) library screen revealed that phosphatase and tensin homologous (PTEN) gene is critical for the regulation of cell survival upon NL101 treatment. The knockout or inhibition of PTEN significantly reduced NL101-induced apoptosis in AML and myelodysplastic syndrome (MDS) cells, accompanied by the activation of protein kinase B (AKT) signaling pathway. The inhibition of mammalian target of rapamycin (mTOR) by rapamycin enhanced the sensitivity of AML cells to NL101-induced cell death. These findings uncover PTEN protein expression as a major determinant of chemosensitivity to NL101 and provide a novel strategy to treat AML with the combination of NL101 and rapamycin.

全基因组CRISPR筛选揭示PTEN基因在急性髓系白血病化疗敏感性中的关键作用

林黎明^1，2，陶菁菁²，孟颖²，甘宜超³，何鑫⁴，李姝⁵，章佳炜¹，高飞琼¹，辛迪佳¹，王璐遥¹，范依丽¹，陈博晓¹，吕志民²，徐旸¹
¹浙江大学医学院附属第二医院血液科，中国杭州市， 310009
²浙江大学医学院附属第一医院和转化医学研究院，浙江省胰腺疾病重点实验室，癌症中心，中国杭州市， 310029
³浙江大学遗传学研究所，中国杭州市， 310058
⁴希望之城贝克曼研究所造血干细胞与白血病研究部，美国加利福尼亚州杜阿尔特市， 91010
⁵上海交通大学医学院附属上海第一人民医院血液科，中国上海市， 200025
摘要：近年来，在急性髓系白血病（AML）治疗的新型靶向药物开发方面虽取得显著进展，但目前化疗仍然是主要的治疗手段，大多数患者的总体生存率仍较低。本研究展示了一种新型小分子化合物NL101的抗白血病活性，该化合物是通过在苯达莫司汀的侧链加上辛二酰苯胺异羟肟酸（SAHA）基团修饰形成。NL101能抑制髓系恶性肿瘤细胞和原发性AML细胞的增殖，并可诱导DNA损伤和半胱天冬酶3介导的细胞凋亡。全基因组CRISPR文库筛选发现，PTEN基因在NL101处理后调节细胞存活中起到关键作用。PTEN敲除或抑制伴随着AKT信号通路的激活，可显著降低AML和骨髓增生异常综合征（MDS）细胞对NL101诱导的凋亡作用。雷帕霉素联用可通过抑制mTOR增强AML细胞对NL101诱导细胞死亡的敏感性。上述发现揭示了PTEN蛋白的表达是NL101化疗敏感性的主要决定因素，这提供了一种新的治疗策略，为NL101与雷帕霉素联合治疗AML提供了理论依据。

关键词组：CRISPR/Case9全基因组敲除文库；PTEN；雷帕霉素；急性髓系白血病；化疗

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全基因组CRISPR筛选揭示PTEN基因在急性髓系白血病化疗敏感性中的关键作用

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