BCL6 antagonizes NOTCH2 to maintain survival of human follicular lymphoma cells Journal Article
| Authors: | Valls, E.; Lobry, C.; Geng, H.; Wang, L.; Cardenas, M.; Rivas, M.; Cerchietti, L.; Oh, P.; Yang, S. N.; Oswald, E.; Graham, C. W.; Jiang, Y.; Hatzi, K.; Agirre, X.; Perkey, E.; Li, Z.; Tam, W.; Bhatt, K.; Leonard, J. P.; Zweidler-McKay, P. A.; Maillard, I.; Elemento, O.; Ci, W.; Aifantis, I.; Melnick, A. |
| Article Title: | BCL6 antagonizes NOTCH2 to maintain survival of human follicular lymphoma cells |
| Abstract: | Although the BCL6 transcriptional repressor is frequently expressed in human follicular lymphomas (FL), its biological role in this disease remains unknown. Herein, we comprehensively identify the set of gene promoters directly targeted by BCL6 in primary human FLs. We noted that BCL6 binds and represses NOTCH2 and NOTCH pathway genes. Moreover, BCL6 and NOTCH2 pathway gene expression is inversely correlated in FL. Notably, BCL6 upregulation is associated with repression of NOTCH2 and its target genes in primary human and murine germinal center (GC) cells. Repression of NOTCH2 is an essential function of BCL6 in FL and GC B cells because inducible expression of Notch2 abrogated GC formation in mice and killed FL cells. Indeed, BCL6-targeting compounds or gene silencing leads to the induction of NOTCH2 activity and compromises survival of FL cells, whereas NOTCH2 depletion or pathway antagonists rescue FL cells from such effects. Moreover, BCL6 inhibitors induced NOTCH2 expression and suppressed growth of human FL xenografts in vivo and primary human FL specimens ex vivo. These studies suggest that established FLs are thus dependent on BCL6 through its suppression of NOTCH2. © 2017 American Association for Cancer Research. |
| Journal Title: | Cancer Discovery |
| Volume: | 7 |
| Issue: | 5 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2017-05-01 |
| Start Page: | 506 |
| End Page: | 521 |
| Language: | English |
| DOI: | 10.1158/2159-8290.cd-16-1189 |
| PROVIDER: | scopus |
| PMCID: | PMC5413414 |
| PUBMED: | 28232365 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 June 2017 -- Source: Scopus |
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