A B Cell Regulome Links Notch to Downstream Oncogenic Pathways in Small B Cell Lymphomas

作者：Ryan Russell J H; Petrovic Jelena; Rausch Dylan M; Zhou Yeqiao; Lareau Caleb A; Kluk Michael J; Christie Amanda L; Lee Winston Y; Tarjan Daniel R; Guo Bingqian; Donohue Laura K H; Gillespie Shawn M; Nardi Valentina; Hochberg Ephraim P; Blacklow Stephen C; Weinstock David M; Faryabi Robert B; Bernstein Bradley E^*; Aster Jon C^*; Pear Warren S^*

来源：Cell Reports, 2017, 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.

• 出版日期2017-10-17
• 单位MIT