Synthetic Lethal and Convergent Biological Effects of Cancer-Associated Spliceosomal Gene Mutations

Publication date: 13 August 2018Source: Cancer Cell, Volume 34, Issue 2Author(s): Stanley Chun-Wei Lee, Khrystyna North, Eunhee Kim, Eunjung Jang, Esther Obeng, Sydney X. Lu, Bo Liu, Daichi Inoue, Akihide Yoshimi, Michelle Ki, Mirae Yeo, Xiao Jing Zhang, Min Kyung Kim, Hana Cho, Young Rock Chung, Justin Taylor, Benjamin H. Durham, Young Joon Kim, Alessandro Pastore, Sebastien MonetteSummaryMutations affecting RNA splicing factors are the most common genetic alterations in myelodysplastic syndrome (MDS) patients and occur in a mutually exclusive manner. The basis for the mutual exclusivity of these mutations and how they contribute to MDS is not well understood. Here we report that although different spliceosome gene mutations impart distinct effects on splicing, they are negatively selected for when co-expressed due to aberrant splicing and downregulation of regulators of hematopoietic stem cell survival and quiescence. In addition to this synthetic lethal interaction, mutations in the splicing factors SF3B1 and SRSF2 share convergent effects on aberrant splicing of mRNAs that promote nuclear factor κB signaling. These data identify shared consequences of splicing-factor mutations and the basis for their mutual exclusivity.Graphical Abstract

Source: Cancer Cell - August 13, 2018 Category: Cancer & Oncology Source Type: research