A B Cell Regulome Links Notch to Downstream Oncogenic Pathways in Small B Cell Lymphomas
| Autor: | Caleb A. Lareau, Robert B. Faryabi, Yeqiao Zhou, Russell J.H. Ryan, Laura Donohue, Amanda L. Christie, David M. Weinstock, Michael J. Kluk, Winston Y. Lee, Shawn M. Gillespie, Jelena Petrovic, Ephraim P. Hochberg, Bingqian Guo, Warren S. Pear, Bradley E. Bernstein, Dylan M. Rausch, Daniel R. Tarjan, Stephen C. Blacklow, Jon C. Aster, Valentina Nardi |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Lymphoma B-Cell Biopsy Chronic lymphocytic leukemia B-cell receptor mantle cell lymphoma Notch signaling pathway lymphoma Regulome MYC Biology medicine.disease_cause Article General Biochemistry Genetics and Molecular Biology Proto-Oncogene Proteins c-myc Mice 03 medical and health sciences 0302 clinical medicine immune system diseases Cell Line Tumor hemic and lymphatic diseases Tumor Microenvironment medicine Animals Humans lcsh:QH301-705.5 Notch signaling B cell Gene Rearrangement B-Lymphocytes Receptors Notch Cell Differentiation Oncogenes Gene rearrangement medicine.disease Xenograft Model Antitumor Assays Gene Expression Regulation Neoplastic Enhancer Elements Genetic 030104 developmental biology medicine.anatomical_structure lcsh:Biology (General) 030220 oncology & carcinogenesis Cancer research chronic lymphocytic leukemia Oncogene MYC Lymph Nodes Carcinogenesis Signal Transduction |
| Zdroj: | Cell Reports, Vol 21, Iss 3, Pp 784-797 (2017) |
| ISSN: | 2211-1247 |
| DOI: | 10.1016/j.celrep.2017.09.066 |
| Popis: | Summary 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. |
| Databáze: | OpenAIRE |
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