Title | Selective targeting of BCL6 induces oncogene addiction switching to BCL2 in B-cell lymphoma. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Dupont, Thibault, Yang Shao Ning, Patel Jayeshkumar, Hatzi Katerina, Malik Alka, Tam Wayne, Martin Peter, Leonard John, Melnick Ari, and Cerchietti Leandro |
Journal | Oncotarget |
Volume | 7 |
Issue | 3 |
Pagination | 3520-32 |
Date Published | 2016 Jan 19 |
ISSN | 1949-2553 |
Keywords | Animals, 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> |
DOI | 10.18632/oncotarget.6513 |
Alternate Journal | Oncotarget |
PubMed ID | 26657288 |
PubMed Central ID | PMC4823124 |