Selective targeting of BCL6 induces oncogene addiction switching to BCL2 in B-cell lymphoma
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Thibault Dupont1,*, ShaoNing Yang1,*, Jayeshkumar Patel1, Katerina Hatzi1, Alka Malik1, Wayne Tam3, Peter Martin1, John Leonard1, Ari Melnick1,2, Leandro Cerchietti1
1Hematology and Oncology Division, Weill Cornell Medical College, New York, NY, USA
2Pharmacology Department, Weill Cornell Medical College, New York, NY, USA
3Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA
*These authors have contributed equally to this work
Ari Melnick, e-mail: email@example.com
Leandro Cerchietti, e-mail: Lec2010@med.cornell.edu
Keywords: lymphoma, BCL6, BCL2, targeting, resistance
Received: July 22, 2015 Accepted: November 21, 2015 Published: December 09, 2015
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.
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