Aneuploidy-inducing gene knockdowns overlap with cancer mutations and identify Orp3 as a B-cell lymphoma suppressor
Aneuploidy-inducing gene knockdowns overlap with cancer mutations and identify Orp3 as a B-cell lymphoma suppressor
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DOI：
10.1038/s41388-019-1073-2
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发表时间：
2020-02-01
期刊：
影响因子：
8
通讯作者：
Rudolph, K. Lenhard
中科院分区：
文献类型：
--
作者：
Njeru, Sospeter N.;Kraus, Johann;Rudolph, K. Lenhard
非整倍体可以刺激肿瘤的发生。然而，控制染色体分离的基因突变在人类肿瘤中很少见，因为这些突变降低了细胞的适应性。筛选实验表明，不直接参与染色体分离的多类基因的敲除可以导致非整倍体的诱导。这些基因在癌症形成中的可能作用仍有待确定。在这里，我们发现了导致检查点缺陷的人类癌细胞非整倍体增加的基因敲除。计算分析显示，已识别的基因与人类癌症中反复发生的突变重叠。三个最强的候选基因(ORP3、GJB3和RXFP1)的敲除增强了培养中人成纤维细胞的恶性转化。此外，Orp3基因敲除导致淋巴祖细胞异常扩张，并导致衰老小鼠染色体不稳定、少克隆的B细胞淋巴瘤的高外显性形成。在肿瘤前阶段，动物的淋巴样细胞表现出磷脂代谢紊乱和增殖调节通路的异常诱导，与造血祖细胞中非整倍体的增加有关。总之，这些结果支持这样的概念，即非整倍体诱导的基因缺陷有助于细胞转化和致癌，包括解除对各种分子过程的调控，如脂质代谢、增殖和细胞生存。
Aneuploidy can instigate tumorigenesis. However, mutations in genes that control chromosome segregation are rare in human tumors as these mutations reduce cell fitness. Screening experiments indicate that the knockdown of multiple classes of genes that are not directly involved in chromosome segregation can lead to aneuploidy induction. The possible contribution of these genes to cancer formation remains yet to be defined. Here we identified gene knockdowns that lead to an increase in aneuploidy in checkpoint-deficient human cancer cells. Computational analysis revealed that the identified genes overlap with recurrent mutations in human cancers. The knockdown of the three strongest selected candidate genes (ORP3, GJB3, and RXFP1) enhances the malignant transformation of human fibroblasts in culture. Furthermore, the knockout of Orp3 results in an aberrant expansion of lymphoid progenitor cells and a high penetrance formation of chromosomal instable, pauci-clonal B-cell lymphoma in aging mice. At pre-tumorous stages, lymphoid cells from the animals exhibit deregulated phospholipid metabolism and an aberrant induction of proliferation regulating pathways associating with increased aneuploidy in hematopoietic progenitor cells. Together, these results support the concept that aneuploidy-inducing gene deficiencies contribute to cellular transformation and carcinogenesis involving the deregulation of various molecular processes such as lipid metabolism, proliferation, and cell survival.