BCL10 is recruited to sites of DNA damage to facilitate DNA double-strand break repair
Authors: Ismail, Ismail Hassan; Dronyk, Ashley; Hu, Xiuying; Hendzel, Michael J.; Shaw, Andrew R.
Recent studies have found BCL10 can localize to the nucleus and that this is linked to tumor aggression and poorer prognosis. These studies suggest that BCL10 localization plays a novel role in the nucleus that may contribute to cellular transformation and carcinogenesis. In this study, we show that BCL10 functions as part of the DNA damage response (DDR). We found that BCL10 facilitates the rapid recruitment of RPA, BRCA1 and RAD51 to sites of DNA damage. Furthermore, we also found that ATM phosphorylates BCL10 in response to DNA damage. Functionally, BCL10 promoted DNA double-strand breaks repair, enhancing cell survival after DNA damage. Taken together our results suggest a novel role for BCL10 in the repair of DNA lesions.
Whole exome sequencing identifies novel mutations of epigenetic regulators in chemorefractory pediatric acute myeloid leukemia
Authors: Zhan, Di; Zhang, Yingchi; Xiao, Peifang; Zheng, Xinchang; Ruan, Min; Zhang, Jingliao; Chen, Aili; Zou, Yao; Chen, Yumei; Huang, Gang; Hu, Shaoyan; Wang, Qian-fei; Zhu, Xiaofan
Genomic alterations underlying chemotherapy resistance remains poorly characterized in pediatric acute myeloid leukemia (AML). In this study, we used whole exome sequencing to identify gene mutations associated with chemo-resistance in 44 pediatric AML patients. We identified previously unreported mutations involving epigenetic regulators such as KDM5C, SRIT6, CHD4, and PRPF6 in pediatric AML patients. Despite low prevalence in general pediatric AML, mutations involving epigenetic regulators including splicing factors, were collectively enriched as a group in primary chemo-resistance AML patients. In addition, clonal evolution analysis of secondary chemo-resistance AML patients reveals dominant clone at diagnosis could survive several course of intensified chemotherapy. And gain of new mutations in genes such as MVP, TCF3, SS18, and BCL10, may contribute to chemo-resistance at relapse. These results provide novel insights into the genetic basis of treatment failure in pediatric AML.