Rationally designed BCL6 inhibitors target activated B cell diffuse large B cell lymphoma
Mariano G. Cardenas, Wenbo Yu, Wendy Beguelin, Matthew R. Teater, Huimin Geng, Rebecca L. Goldstein, Erin Oswald, Katerina Hatzi, Shao-Ning Yang, Joanna Cohen, Rita Shaknovich, Kenno Vanommeslaeghe, Huimin Cheng, Dongdong Liang, Hyo Je Cho, Joshua Abbott, Wayne Tam, Wei Du, John P. Leonard, Olivier Elemento, Leandro Cerchietti, Tomasz Cierpicki, Fengtian Xue, Alexander D. MacKerell Jr., Ari M. Melnick
Mariano G. Cardenas, Wenbo Yu, Wendy Beguelin, Matthew R. Teater, Huimin Geng, Rebecca L. Goldstein, Erin Oswald, Katerina Hatzi, Shao-Ning Yang, Joanna Cohen, Rita Shaknovich, Kenno Vanommeslaeghe, Huimin Cheng, Dongdong Liang, Hyo Je Cho, Joshua Abbott, Wayne Tam, Wei Du, John P. Leonard, Olivier Elemento, Leandro Cerchietti, Tomasz Cierpicki, Fengtian Xue, Alexander D. MacKerell Jr., Ari M. Melnick
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Research Article Oncology

Rationally designed BCL6 inhibitors target activated B cell diffuse large B cell lymphoma

Abstract

Diffuse large B cell lymphomas (DLBCLs) arise from proliferating B cells transiting different stages of the germinal center reaction. In activated B cell DLBCLs (ABC-DLBCLs), a class of DLBCLs that respond poorly to current therapies, chromosomal translocations and amplification lead to constitutive expression of the B cell lymphoma 6 (BCL6) oncogene. The role of BCL6 in maintaining these lymphomas has not been investigated. Here, we designed small-molecule inhibitors that display higher affinity for BCL6 than its endogenous corepressor ligands to evaluate their therapeutic efficacy for targeting ABC-DLBCL. We used an in silico drug design functional-group mapping approach called SILCS to create a specific BCL6 inhibitor called FX1 that has 10-fold greater potency than endogenous corepressors and binds an essential region of the BCL6 lateral groove. FX1 disrupted formation of the BCL6 repression complex, reactivated BCL6 target genes, and mimicked the phenotype of mice engineered to express BCL6 with corepressor binding site mutations. Low doses of FX1 induced regression of established tumors in mice bearing DLBCL xenografts. Furthermore, FX1 suppressed ABC-DLBCL cells in vitro and in vivo, as well as primary human ABC-DLBCL specimens ex vivo. These findings indicate that ABC-DLBCL is a BCL6-dependent disease that can be targeted by rationally designed inhibitors that exceed the binding affinity of natural BCL6 ligands.

Authors

Mariano G. Cardenas, Wenbo Yu, Wendy Beguelin, Matthew R. Teater, Huimin Geng, Rebecca L. Goldstein, Erin Oswald, Katerina Hatzi, Shao-Ning Yang, Joanna Cohen, Rita Shaknovich, Kenno Vanommeslaeghe, Huimin Cheng, Dongdong Liang, Hyo Je Cho, Joshua Abbott, Wayne Tam, Wei Du, John P. Leonard, Olivier Elemento, Leandro Cerchietti, Tomasz Cierpicki, Fengtian Xue, Alexander D. MacKerell Jr., Ari M. Melnick

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Figure 3

FX1 phenocopies the BCL6 mutant phenotype.

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FX1 phenocopies the BCL6 mutant phenotype. Ten C57BL/6 mice were immuniz...
Ten C57BL/6 mice were immunized with sheep red blood cells and then treated i.p. with 80 mg/kg/d FX1 or vehicle alone daily for 8 days starting 48 hours after immunization. (A) Spleen weights from mice treated with FX1 or vehicle (2-tailed Mann-Whitney unpaired test). (B) Flow cytometry quantification of total B cells (B220+) (t test). (C) Flow cytometry quantification of GC B cells (B220+DAPI–GL7+FAS+, t test). (D) IHC of spleens from mice treated with FX1 or vehicle and stained with peanut agglutinin (PNA), Ki-67, and B220. Scale bars: 500 μm. Quantification of number and area of GCs was performed by ImageJ software. The y axis shows number of positive cells/total cell number of different sections of spleens (n = 10) (2-tailed Mann-Whitney unpaired test). Values in A–D are shown as mean ± SEM.