BCL6 Antagonizes NOTCH2 to Maintain Survival of Human Follicular Lymphoma Cells

Valls, Ester; Lobry, Camille; Geng, Huimin; Wang, Ling; Cárdenas, Mariano; Rivas, Martín A.; Cerchietti, Leandro; Oh, Phil; Yang, Shao Ning; Oswald, Erin; Graham, Camille W.; Jiang, Yanwen; Hatzi, Katerina; Agirre, Xabier; Perkey, Eric; Li, Zhuoning; Tam, Wayne; Bhatt, Kamala; Leonard, John P.; Zweidler‐McKay, Patrick A.; Maillard, Ivan; Elemento, Olivier; Ci, Weimin; Aifantis, Iannis; Melnick, Ari

doi:10.1158/2159-8290.cd-16-1189

Cited by 46 publications

(50 citation statements)

References 46 publications

(77 reference statements)

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“…© 2020 American Association for Cancer cancerdiscovery.aacrjournals.org Downloaded from Published OnlineFirst January 8, 2020; DOI: 10.1158/2159-8290.CD-19-0116 regulated through this mechanism (3). Importantly, as a variety of GCB-derived malignancies rely on BCL6 function independently of CREBBP or EZH2 mutation (38,39), opposing this function through HDAC3 inhibition may also be effective in tumors without these genetic alterations. We have shown preliminary evidence in the primary setting using DLBCL PDX models.…”

Section: Discussionmentioning

confidence: 99%

Selective Inhibition of HDAC3 Targets Synthetic Vulnerabilities and Activates Immune Surveillance in Lymphoma

et al. 2020

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CREBBP mutations are highly recurrent in B-cell lymphomas and either inactivate its histone acetyltransferase (HAT) domain or truncate the protein. Herein, we show that these two classes of mutations yield different degrees of disruption of the epigenome, with HAT mutations being more severe and associated with inferior clinical outcome. Genes perturbed by CREBBP mutation are direct targets of the BCL6-HDAC3 onco-repressor complex. Accordingly, we show that HDAC3-selective inhibitors reverse CREBBP-mutant aberrant epigenetic programming, resulting in: (i) growth inhibition of lymphoma cells through induction of BCL6 target genes such as CDKN1A and (ii) restoration of immune surveillance due to induction of BCL6-repressed IFN pathway and antigen-presenting genes. By reactivating these genes, exposure to HDAC3 inhibitors restored the ability of tumor-infi ltrating lymphocytes to kill DLBCL cells in an MHC class I and II-dependent manner, and synergized with PD-L1 blockade in a syngeneic model in vivo. Hence, HDAC3 inhibition represents a novel mechanism-based immune epigenetic therapy for CREBBP-mutant lymphomas. SIGNIFICANCE: We have leveraged the molecular characterization of different types of CREBBP mutations to defi ne a rational approach for targeting these mutations through selective inhibition of HDAC3. This represents an attractive therapeutic avenue for targeting synthetic vulnerabilities in CREBBPmutant cells in tandem with promoting antitumor immunity.

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Section: Discussionmentioning

confidence: 99%

Selective Inhibition of HDAC3 Targets Synthetic Vulnerabilities and Activates Immune Surveillance in Lymphoma

et al. 2020

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“…Evolutionarily, the first recognizable BCL6 gene appeared over 500 million years ago in early vertebrates. 84,86 To drive the GC phenotype, BCL6 binds and represses genes The C1/BN2, C5/MCD and N1 subtypes colored in pink, purple and orange respectively, are mostly ABC-related. 85 Presumably, the existence of BCL6 as an inducible stress tolerance protein facilitated evolution of the humoral immune response, where B cells must be able to tolerate the major stresses associated with massive proliferation and mutagenesis.…”

Section: Bcland Control Of the G C Phenot Ypementioning

confidence: 99%

“…85 Lymphoma cells inherit dependency on BCL6 from their GC cell-of-origin and are almost universally dependent on BCL6 for their survival and proliferation. 84,86 To drive the GC phenotype, BCL6 binds and represses genes linked to DNA damage response (eg, ATR, TP53, etc.) cell cycle checkpoint control (eg, CDKN1A, CDKN1B, etc.)…”

Section: Bcland Control Of the G C Phenot Ypementioning

confidence: 99%

Germinal center‐derived lymphomas: The darkest side of humoral immunity

Mlynarczyk

Fontán

Melnick

2019

Immunological Reviews

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125

142

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Summary One of the unusual features of germinal center (GC) B cells is that they manifest many hallmarks of cancer cells. Accordingly, most B‐cell neoplasms originate from the GC reaction, and characteristically display abundant point mutations, structural genomic lesions, and clonal diversity from the genetic and epigenetic standpoints. The dominant biological theme of GC‐derived lymphomas is mutation of genes involved in epigenetic regulation and immune receptor signaling, which come into play at critical transitional stages of the GC reaction. Hence, mechanistic studies of these mutations reveal fundamental insight into the biology of the normal and malignant GC B cell. The BCL6 transcription factor plays a central role in establishing the GC phenotype in B cells, and most lymphomas are dependent on BCL6 to maintain survival, proliferation, and perhaps immune evasion. Many lymphoma mutations have the commonality of enhancing the oncogenic functions of BCL6, or overcoming some of its tumor suppressive effects. Herein, we discuss how unique features of the GC reaction create vulnerabilities that select for particular lymphoma mutations. We examine the interplay between epigenetic programming, metabolism, signaling, and immune regulatory mechanisms in lymphoma, and discuss how these are leading to novel precision therapy strategies to treat lymphoma patients.

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“…Virtually all of the HDAC3 corepressor complexes present in DLBCL cells are bound with BCL6, suggesting that HDAC3 inhibitors effect is largely explained by their depression of the subset of BCL6 target genes regulated through this mechanism 3 . Importantly, as a variety of GCB-derived malignancies rely on BCL6 function independently of CREBBP or EZH2 mutation 33,34 , opposing this function through HDAC3 inhibition may also be effective in tumors without these genetic alterations. We have shown preliminary evidence in the primary setting using DLBCL PDX models, for which CREBBP mutant tumors were not currently available.…”

Section: Discussionmentioning

confidence: 99%

Selective inhibition of HDAC3 targets synthetic vulnerabilities and activates immune surveillance in lymphoma

Mondello

Tadros

Teater

et al. 2019

Preprint

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45 46CREBBP mutations are highly recurrent in B-cell lymphomas and either inactivate its 47 histone acetyltransferase (HAT) domain or truncate the protein. Herein, we show that 48 these two classes of mutations yield different degrees of disruption of the epigenome, 49 with HAT mutations being more severe and associated with inferior clinical outcome. 50 Genes perturbed by CREBBP mutation are direct targets of the BCL6/HDAC3 onco-51 repressor complex. Accordingly, we show that HDAC3 selective inhibitors fully reverse 52 CREBBP mutant aberrant epigenetic programming resulting in: a) growth inhibition of 53 lymphoma cells through induction of BCL6 target genes such as CDKN1A and b) 54 restoration of immune surveillance due to induction of BCL6 repressed IFN pathway and 55 antigen presentation genes. By reactivating these genes, exposure to HDAC3-i restored 56 the ability of tumor infiltrating lymphocytes to kill DLBCL cells in an MHC II and MHC I 57 dependent manner. Hence HDAC3-i represent a novel mechanism-based immune-58 epigenetic therapy for CREBBP mutant lymphomas. 59 60 61 62 We have leveraged the molecular characterization of different types of CREBBP 63 mutations to define a rational approach for targeting these mutations through selective 64 inhibition of HDAC3. This represents an attractive therapeutic avenue for targeting 65 synthetic vulnerabilities in CREBBP mutant cells in tandem with promoting anti-tumor 66 immunity. 67 68 69 70 Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) are the two most 71 frequent subtypes of non-Hodgkin lymphoma. These diseases originate from germinal 72 center B (GCB)-cells; a stage of development that naturally allows for the proliferation 73 and affinity maturation of antigen-experienced B-cells to produce terminally-differentiated 74 memory B-cells or plasma cells. The germinal center (GC) reaction is regulated by B-cell-75 intrinsic activation and suppression of large sets of genes by master regulators such as 76 the BCL6 transcription factor 1 , and extrinsically via the interaction of GCB-cells with 77 follicular helper T (TFH)-cells and other immune cells within the GC 2 . The BCL6 78 transcription factor is critical for GCB-cell development and coordinately suppresses the 79 expression of large sets of genes by recruiting SMRT and NCOR co-repressor complexes 80 containing HDAC3 3 and tethering a non-canonical polycomb repressor 1-like complex in 81 cooperation with EZH2 4 . These genes are normally reactivated to drive GC exit and 82 terminal differentiation, but the epigenetic control of these dynamically-regulated GC 83 transcriptional programs is perturbed in DLBCL and FL via the downstream effects of 84 somatic mutation of chromatin modifying genes 5 (CMG). 85 86 STATEMENT OF SIGNIFICANCEThe second most frequently mutated CMG in both DLBCL and FL is the CREBBP gene, 87 which encodes a histone acetyltransferase that activates transcription via acetylation of 88 histone H3 lysine 27 (H3K27Ac) and other residues. We have previously fo...

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BCL6 Antagonizes NOTCH2 to Maintain Survival of Human Follicular Lymphoma Cells

Cited by 46 publications

References 46 publications

Selective Inhibition of HDAC3 Targets Synthetic Vulnerabilities and Activates Immune Surveillance in Lymphoma

Selective Inhibition of HDAC3 Targets Synthetic Vulnerabilities and Activates Immune Surveillance in Lymphoma

Germinal center‐derived lymphomas: The darkest side of humoral immunity

Selective inhibition of HDAC3 targets synthetic vulnerabilities and activates immune surveillance in lymphoma

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