TitleSelective targeting of BCL6 induces oncogene addiction switching to BCL2 in B-cell lymphoma.
Publication TypeJournal Article
Year of Publication2016
AuthorsDupont, Thibault, Yang Shao Ning, Patel Jayeshkumar, Hatzi Katerina, Malik Alka, Tam Wayne, Martin Peter, Leonard John, Melnick Ari, and Cerchietti Leandro
JournalOncotarget
Volume7
Issue3
Pagination3520-32
Date Published2016 Jan 19
ISSN1949-2553
KeywordsAnimals, Biphenyl Compounds, Blotting, Western, Cell Proliferation, Drug Resistance, Neoplasm, Humans, Indoles, Lymphoma, Large B-Cell, Diffuse, Male, Mice, Mice, Nude, Nitrophenols, Peptide Fragments, Piperazines, Proto-Oncogene Proteins, Proto-Oncogene Proteins c-bcl-2, Proto-Oncogene Proteins c-bcl-6, Pyrroles, Rats, Rats, Sprague-Dawley, RNA, Small Interfering, Sulfonamides, Tumor Cells, Cultured, Xenograft Model Antitumor Assays
Abstract

<p>The BCL6 oncogene plays a crucial role in sustaining diffuse large B-cell lymphomas (DLBCL) through transcriptional repression of key checkpoint genes. BCL6-targeted therapy kills lymphoma cells by releasing these checkpoints. However BCL6 also directly represses several DLBCL oncogenes such as BCL2 and BCL-XL that promote lymphoma survival. Herein we show that DLBCL cells that survive BCL6-targeted therapy induce a phenomenon of "oncogene-addiction switching" by reactivating BCL2-family dependent anti-apoptotic pathways. Thus, most DLBCL cells require concomitant inhibition of BCL6 and BCL2-family members for effective lymphoma killing. Moreover, in DLBCL cells initially resistant to BH3 mimetic drugs, BCL6 inhibition induces a newly developed reliance on anti-apoptotic BCL2-family members for survival that translates in acquired susceptibility to BH3 mimetic drugs ABT-737 and obatoclax. In germinal center B cell-like (GCB)-DLBCL cells, the proteasome inhibitor bortezomib and the NEDD inhibitor MLN4924 post-transcriptionally activated the BH3-only sensitizer NOXA thus counteracting the oncogenic switch to BCL2 induced by BCL6-targeting. Hence our study indicates that BCL6 inhibition induces an on-target feedback mechanism based on the activation of anti-apoptotic BH3 members. This oncogene-addition switching mechanism was harnessed to develop rational combinatorial therapies for GCB-DLBCL. </p>

DOI10.18632/oncotarget.6513
Alternate JournalOncotarget
PubMed ID26657288
PubMed Central IDPMC4823124