Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota.
Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
Mol Cancer Res. 2019 Feb;17(2):567-582. doi: 10.1158/1541-7786.MCR-18-0582. Epub 2018 Oct 24.
Follicular lymphoma and diffuse large B-cell lymphoma (DLBCL) are the most common non-Hodgkin lymphomas distinguishable by unique mutations, chromosomal rearrangements, and gene expression patterns. Here, it is demonstrated that early B-cell progenitors express 2',3'-cyclic-nucleotide 3' phosphodiesterase (CNP) and that when targeted with () mutagenesis, mutation or loss gave rise to highly penetrant lymphoid diseases, predominantly follicular lymphoma and DLBCL. In efforts to identify the genetic drivers and signaling pathways that are functionally important in lymphomagenesis, SB transposon insertions were analyzed from splenomegaly specimens of -mutagenized mice ( = 23) and -mutagenized mice on a background ( = 7) and identified 48 and 12 sites with statistically recurrent transposon insertion events, respectively. Comparison with human data sets revealed novel and known driver genes for B-cell development, disease, and signaling pathways: PI3K-AKT-mTOR, MAPK, NFκB, and B-cell receptor (BCR). Finally, functional data indicate that modulating Ras-responsive element-binding protein 1 (RREB1) expression in human DLBCL cell lines alters KRAS expression, signaling, and proliferation; thus, suggesting that this proto-oncogene is a common mechanism of RAS/MAPK hyperactivation in human DLBCL. IMPLICATIONS: A forward genetic screen identified new genetic drivers of human B-cell lymphoma and uncovered a RAS/MAPK-activating mechanism not previously appreciated in human lymphoid disease. Overall, these data support targeting the RAS/MAPK pathway as a viable therapeutic target in a subset of human patients with DLBCL.
滤泡性淋巴瘤和弥漫性大 B 细胞淋巴瘤（DLBCL）是最常见的非霍奇金淋巴瘤，可以通过独特的突变、染色体重排和基因表达模式来区分。在这里，研究表明早期 B 细胞前体细胞表达 2'、3'-环核苷酸 3' 磷酸二酯酶（CNP），当用 () 诱变靶向时， 突变或 缺失导致高穿透性的淋巴样疾病，主要是滤泡性淋巴瘤和 DLBCL。为了鉴定在淋巴瘤发生中具有功能重要性的遗传驱动因素和信号通路，对 () 诱变的小鼠（=23）和 () 诱变的小鼠的脾肿大标本中的 SB 转座子插入进行了分析（在 背景下）（=7），并分别鉴定了 48 和 12 个具有统计学上重复转座子插入事件的位点。与人类数据集的比较揭示了用于 B 细胞发育、疾病和信号通路的新的和已知的驱动基因：PI3K-AKT-mTOR、MAPK、NFκB 和 B 细胞受体（BCR）。最后，功能数据表明，在人 DLBCL 细胞系中调节 Ras 反应元件结合蛋白 1（RREB1）的表达改变 KRAS 的表达、信号和增殖；因此，表明该原癌基因是人类 DLBCL 中 RAS/MAPK 过度激活的常见机制。意义：正向遗传筛选确定了人类 B 细胞淋巴瘤的新遗传驱动因素，并揭示了以前在人类淋巴样疾病中未被认识到的 RAS/MAPK 激活机制。总体而言，这些数据支持将 RAS/MAPK 通路作为人类一部分 DLBCL 患者可行的治疗靶点。
