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

by Felix Oppel, Ting Tao, Hui Shi, Kenneth N. Ross, Mark W. Zimmerman, Shuning He, Guangxiang Tong, Jon C. Aster, A. Thomas Look 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 it s target genes. To further define the role of inactivatingATRX mutations in carcinogenesis, we knocked outatrx in our previously reportedp53/nf1-deficient zebrafish line that develops malignant peripheral nerve sheath tumors and gliomas. Complete inactivation ofatrx using CRISPR/Cas9 was lethal in developing fish and resulted in an alpha-thalassemia-like phenotype including reduced alpha-globin expression. Inp53/nf1-deficient zebrafish neither peripheral nerve sheath tumors nor gliomas showed accelerated onset inatrx+/- fish, but these fish developed various tumors that were not observed in theiratrx+/+ 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 mutantATRX, indicating that our zebrafish model reliably mimics a role forATRX-loss in the early pathogenesis of these human cancer types. RNA-seq ofp53/nf1- andp53/nf1/atrx-deficient tumors revealed that down-regulation of telomerase accompanied A...
Source: PLoS Genetics - Category: Genetics & Stem Cells Authors: Source Type: research