A B Cell Regulome Links Notch to Downstream Oncogenic Pathways in Small B Cell Lymphomas
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
Affiliations
Russell J.H. Ryan
Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA
Jelena Petrovic
Department of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Dylan M. Rausch
Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA
Yeqiao Zhou
Department of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Caleb A. Lareau
Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA
Michael J. Kluk
Department of Pathology, Weill Cornell School of Medicine, New York, NY 10065, USA
Amanda L. Christie
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
Winston Y. Lee
Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115, USA
Daniel R. Tarjan
Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA
Bingqian Guo
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
Laura K.H. Donohue
Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA
Shawn M. Gillespie
Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA
Valentina Nardi
Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA
Ephraim P. Hochberg
Department of Medicine, MGH Cancer Center, Massachusetts General Hospital, Boston, MA 02140, USA
Stephen C. Blacklow
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
David M. Weinstock
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
Robert B. Faryabi
Department of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
Bradley E. Bernstein
Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA
Jon C. Aster
Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115, USA
Warren S. Pear
Department of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA
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.
