A B Cell Regulome Links Notch to Downstream Oncogenic Pathways in Small B Cell Lymphomas.
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.
|Year of Publication
2017 Oct 17
|PubMed Central ID
R01 AI047833 / AI / NIAID NIH HHS / United States
DP1 CA216873 / CA / NCI NIH HHS / United States
P30 DK050306 / DK / NIDDK NIH HHS / United States
R01 CA092433 / CA / NCI NIH HHS / United States
U54 HG004570 / HG / NHGRI NIH HHS / United States
K08 CA208013 / CA / NCI NIH HHS / United States
P30 CA016520 / CA / NCI NIH HHS / United States
R35 CA220340 / CA / NCI NIH HHS / United States
S10 OD016372 / OD / NIH HHS / United States
P01 CA119070 / CA / NCI NIH HHS / United States