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Loss of atrx cooperates with p53-deficiency to promote the development of sarcomas and other malignancies

文献类型： 外文期刊

作者： Oppel, Felix 1 ; Tao, Ting 1 ; Shi, Hui 1 ; Ross, Kenneth N. 1 ; Zimmerman, Mark W. 1 ; He, Shuning 1 ; Tong, Guangxia 1 ;

作者机构： 1.Harvard Med Sch, Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02115 USA

2.Chinese Acad Fishery Sci, Heilongjiang River Fisheries Res Inst, Harbin, Heilongjiang, Peoples R China

3.Harvard Med Sch, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

期刊名称：PLOS GENETICS （ 影响因子：5.917； 五年影响因子：6.284 ）

ISSN： 1553-7404

年卷期： 2019 年 15 卷 4 期

页码：

收录情况： SCI

摘要： The SWI/SNF-family chromatin remodeling protein ATRX is a tumor suppressor in sarcomas, gliomas and other malignancies. Its loss of function facilitates the alternative lengthening of telomeres (ALT) pathway in tumor cells, while it also affects Polycomb repressive complex 2 (PRC2) silencing of its target genes. To further define the role of inactivating ATRX mutations in carcinogenesis, we knocked out atrx in our previously reported p53/nf1-deficient zebrafish line that develops malignant peripheral nerve sheath tumors and gliomas. Complete inactivation of atrx using CRISPR/Cas9 was lethal in developing fish and resulted in an alpha-thalassemia-like phenotype including reduced alpha-globin expression. In p53/nf1-deficient zebrafish neither peripheral nerve sheath tumors nor gliomas showed accelerated onset in atrx+/- fish, but these fish developed various tumors that were not observed in their atrx+/+ siblings, including epithelioid sarcoma, angiosarcoma, undifferentiated pleomorphic sarcoma and rare types of carcinoma. These cancer types are included in the AACR Genie database of human tumors associated with mutant ATRX, indicating that our zebrafish model reliably mimics a role for ATRX-loss in the early pathogenesis of these human cancer types. RNA-seq of p53/nf1- and p53/nf1/atrx-deficient tumors revealed that down-regulation of telomerase accompanied ALT-mediated lengthening of the telomeres in atrx-mutant samples. Moreover, inactivating mutations in atrx disturbed PRC2-target gene silencing, indicating a connection between ATRX loss and PRC2 dysfunction in cancer development. Author summary Somatic mutations in genes coding for epigenetic regulators such as ATRX are found across a diverse group of cancer types, suggesting their broad relevance in tumor induction and progression. However, tumors that have been linked to these chromatin remodelers can arise in many different molecular and cellular contexts, requiring studies with new experimental models to understand the extent and mechanisms of tumor development mediated by these regulatory proteins. Thus, we analyzed the tumor suppressive role of atrx in zebrafish that already harbored inactivating mutations of p53 and nf1. Homozygous deletion of atrx was lethal in developing fish, whereas the partial loss of this gene (atrx+/-) within the p53/nf1-deficient background led to a diverse spectrum of tumors not observed in animals that were wildtype for atrx, including epithelioid sarcoma, angiosarcoma, and rare carcinomas. Most of the cancer types we identified correspond to human tumors in the ATRX-mutant tumor sample cohort within the AACR Genie database, attesting to the relevance of our findings to human cancer. Further analysis revealed downregulation of telomerase during the lengthening of the telomeres through the ALT pathway, and disturbed function of the polycomb repressive complex 2 as key mechanistic components underlying atrx-linked tumorigenesis. These results demonstrate how a p53/nf1 compromised genetic background combined with ATRX haploinsufficiency leads to a broad spectrum of sarcomas and carcinomas associated with loss of this chromatin modulator.

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