title: Selective targeting of BCL6 induces oncogene addiction switching to BCL2 in B-cell lymphoma.
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 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.
authors.affiliation: Hematology and Oncology Division, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Thibault
authors.initials: T
authors.lastname: Dupont
authors.affiliation: Hematology and Oncology Division, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Shao Ning
authors.initials: SN
authors.lastname: Yang
authors.affiliation: Hematology and Oncology Division, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Jayeshkumar
authors.initials: J
authors.lastname: Patel
authors.affiliation: Hematology and Oncology Division, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Katerina
authors.initials: K
authors.lastname: Hatzi
authors.affiliation: Hematology and Oncology Division, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Alka
authors.initials: A
authors.lastname: Malik
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Wayne
authors.initials: W
authors.lastname: Tam
authors.affiliation: Hematology and Oncology Division, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Martin
authors.affiliation: Hematology and Oncology Division, Weill Cornell Medical College, New York, NY, USA.
authors.forename: John
authors.initials: J
authors.lastname: Leonard
authors.affiliation: Hematology and Oncology Division, Weill Cornell Medical College, New York, NY, USA.|Pharmacology Department, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
authors.affiliation: Hematology and Oncology Division, Weill Cornell Medical College, New York, NY, USA.
authors.forename: Leandro
authors.initials: L
authors.lastname: Cerchietti
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D007211:Indoles; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009596:Nitrophenols / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C501332:ABT-737; C000595707:BCL2 protein, human; C084103:BCL6 protein, human; C474007:Bax protein (53-86); D001713:Biphenyl Compounds; D007211:Indoles; D009596:Nitrophenols; D010446:Peptide Fragments; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051560:Proto-Oncogene Proteins c-bcl-6; D011758:Pyrroles; D034741:RNA, Small Interfering; D013449:Sulfonamides; C520962:obatoclax
keywords: BCL2; BCL6; lymphoma; resistance; targeting