Selective targeting of BCL6 induces oncogene addiction switching to BCL2 in B-cell lymphoma

Thibault Dupont, Shao Ning Yang, Jayeshkumar Patel, Katerina Hatzi, Alka Malik, Wayne Tam, Peter Martin, John Leonard, Ari Melnick, Leandro Cerchietti

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

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 posttranscriptionally 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.

Original languageEnglish (US)
Pages (from-to)3520-3532
Number of pages13
JournalOncotarget
Volume7
Issue number3
DOIs
StatePublished - Jan 1 2016

Keywords

  • BCL2
  • BCL6
  • Lymphoma
  • Resistance
  • Targeting

ASJC Scopus subject areas

  • Oncology

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    Dupont, T., Yang, S. N., Patel, J., Hatzi, K., Malik, A., Tam, W., Martin, P., Leonard, J., Melnick, A., & Cerchietti, L. (2016). Selective targeting of BCL6 induces oncogene addiction switching to BCL2 in B-cell lymphoma. Oncotarget, 7(3), 3520-3532. https://doi.org/10.18632/oncotarget.6513