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

Publication date: 17 October 2017
Source:Cell Reports, Volume 21, Issue 3
Author(s): Russell J.H. Ryan, Jelena Petrovic, Dylan M. Rausch, Yeqiao Zhou, Caleb A. Lareau, Michael J. Kluk, Amanda L. Christie, Winston Y. Lee, Daniel R. Tarjan, Bingqian Guo, Laura K.H. Donohue, Shawn M. Gillespie, Valentina Nardi, Ephraim P. Hochberg, Stephen C. Blacklow, David M. Weinstock, Robert B. Faryabi, Bradley E. Bernstein, Jon C. Aster, Warren S. Pear
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.

Graphical abstract

Teaser

Ryan et al. reveal targets of Notch signaling in B cell cancers associated with Notch gain-of-function mutations. Many Notch-responsive genes are part of pathways implicated in B cell cancer pathogenesis. These findings provide insights into the role of Notch and a rationale for targeting Notch in B cell cancers.


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