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

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

doi:10.1016/j.celrep.2017.09.066

Abstract

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 Bcell 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 Bcell malignancies and have important implications for therapeutic targeting of Notch-dependent oncogenic pathways.

Highlights

Notch signaling controls development and tissue homeostasis in metazoan animals and when dysregulated contributes to the pathogenesis of several hematologic malignancies and solid tumors
Signaling relies on ligand-mediated proteolysis of Notch receptors by gamma-secretase, which releases the Notch intracellular domain (NICD), allowing it to translocate to the nucleus and form a Notch transcription complex (NTC) with the DNA-binding factor RBPJ and co-activators of the Mastermind-like (MAML) family
Notch-Addicted mantle cell lymphoma (MCL) Cell Lines Bear Activating Notch Gene Rearrangements The growth of the MCL cell lines Rec-1 and SP-49 is suppressed by gamma-secretase inhibitors (GSI) (Figure S1A) and by dominant-negative MAML1 (Kridel et al, 2012), features that identify ‘‘Notch-addicted’’ cell lines (Weng et al, 2004)

Summary

Introduction

Notch signaling controls development and tissue homeostasis in metazoan animals (reviewed in Bray, 2016) and when dysregulated contributes to the pathogenesis of several hematologic malignancies and solid tumors (reviewed in Aster et al, 2017). NTCs recruit factors such as p300 and Mediator and activate Notch target gene expression. Outcomes produced by Notch signaling are cell context-specific, presumably because Notch drives distinct gene expression programs in different cell types. Both gain- and loss-of-function Notch mutations are observed in various human cancers, indicating that Notch can be oncogenic or tumor suppressive depending on cell context. Detailed descriptions of Notch target genes and linked regulatory elements have been confined to a single cancer, T cell acute lymphoblastic leukemia (T-ALL) (Wang et al, 2014), in which Notch has an oncogenic role

Results

Discussion

Conclusion