Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA; Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA.
Department of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Cell Rep. 2017 Oct 17;21(3):784-797. doi: 10.1016/j.celrep.2017.09.066.
Gain-of-function Notch mutations are recurrent in mature small B cell lymphomas such as mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL), but the Notch target genes that contribute to B cell oncogenesis are largely unknown. We performed integrative analysis of Notch-regulated transcripts, genomic binding of Notch transcription complexes, and genome conformation data to identify direct Notch target genes in MCL cell lines. This B cell Notch regulome is largely controlled through Notch-bound distal enhancers and includes genes involved in B cell receptor and cytokine signaling and the oncogene MYC, which sustains proliferation of Notch-dependent MCL cell lines via a Notch-regulated lineage-restricted enhancer complex. Expression of direct Notch target genes is associated with Notch activity in an MCL xenograft model and in CLL lymph node biopsies. Our findings provide key insights into the role of Notch in MCL and other B cell malignancies and have important implications for therapeutic targeting of Notch-dependent oncogenic pathways.
功能获得性 Notch 突变在成熟小 B 细胞淋巴瘤中（如套细胞淋巴瘤 [MCL] 和慢性淋巴细胞白血病 [CLL]）频繁发生，但促成 B 细胞肿瘤发生的 Notch 靶基因在很大程度上是未知的。我们对 Notch 调控转录本、Notch 转录复合物的基因组结合以及基因组构象数据进行了综合分析，以鉴定 MCL 细胞系中的直接 Notch 靶基因。这个 B 细胞 Notch 调控组主要通过 Notch 结合的远端增强子来控制，包括参与 B 细胞受体和细胞因子信号以及癌基因 MYC 的基因，后者通过 Notch 调控的谱系特异性增强子复合物维持 Notch 依赖性 MCL 细胞系的增殖。直接 Notch 靶基因的表达与 MCL 异种移植模型和 CLL 淋巴结活检中的 Notch 活性相关。我们的发现为 Notch 在 MCL 和其他 B 细胞恶性肿瘤中的作用提供了重要的见解，并对 Notch 依赖性致癌途径的治疗靶向具有重要意义。
