Year: 2017
Type: article
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 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.
Source: Cell Reports
Authors: 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
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,620
Funders: Leukemia and Lymphoma Society, Massachusetts General Hospital, University of Pennsylvania, Abramson Cancer Center, National Institutes of Health, Harvard Stem Cell Institute, National Human Genome Research Institute, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: G1403651065, Structure and function in Notch Signaling, G3536620572, G3968619285, Influx Flow Cytometer, G499207949, G522626033, Oncogenic programs driven by notch signaling in B-cell lymphoma, High-throughput sequencing of chromatin regulatory elements, G6694682254, G7461558928, G8033360758, G9000005079, G9000056318, G9000286486, Center for Molecular Studies in Digestive and Liver Diseases
OpenAlex ID: W2765543597