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

16 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
Publication statusPublished - 2016

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Keywords

  • BCL2
  • BCL6
  • Lymphoma
  • Resistance
  • Targeting

ASJC Scopus subject areas

  • Oncology

Cite this

Dupont, T., Yang, S. N., Patel, J., Hatzi, K., Malik, A., Tam, W., ... 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