The CREBBP Acetyltransferase Is a Haploinsufficient Tumor Suppressor in B-cell Lymphoma

Zhang, Jiyuan; Vlasevska, Sofija; Wells, Victoria A.; Nataraj, Sarah; Holmes, Antony B.; Duval, Romain; Meyer, Stefanie N.; Mo, Tongwei; Basso, Katia; Brindle, Paul K.; Hussein, Shafinaz; Dalla‐Favera, Riccardo; Pasqualucci, Laura

doi:10.1158/2159-8290.cd-16-1417

Cited by 194 publications

(248 citation statements)

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“…While this paper was under review, 2 papers interrogating the role of Crebbp inactivation in murine B-cell lymphoma models were published. 34,49 Jiang et al reported downregulation of MHC class II genes with short hairpin RNA-mediated knock-down of Crebbp, but this was not reported by Zhang et al, using B-cell-specific deletion of Crebbp with cre recombinase, and only modest changes were shown in our study. The role of Crebbp loss compared with Crebbp KATdomain point mutation in the deregulation of MHC class II expression therefore requires further functional interrogation.…”

Section: Discussioncontrasting

confidence: 90%

Crebbp loss cooperates with Bcl2 overexpression to promote lymphoma in mice

García-Ramírez

Tadros

González-Herrero

et al. 2017

Blood

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• Crebbp inactivation perturbs B-cell development, but cooperates with Bcl2 overexpression to promote lymphoma.• Transcriptional and epigenetic signatures of Crebbp loss implicate Myc in disease etiology.CREBBP is targeted by inactivating mutations in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). Here, we provide evidence from transgenic mouse models that Crebbp deletion results in deficits in B-cell development and can cooperate with Bcl2 overexpression to promote B-cell lymphoma. Through transcriptional and epigenetic profiling of these B cells, we found that Crebbp inactivation was associated with broad transcriptional alterations, but no changes in the patterns of histone acetylation at the proximal regulatory regions of these genes. However, B cells with Crebbp inactivation showed high expression of Myc and patterns of altered histone acetylation that were localized to intragenic regions, enriched for Myc DNA binding motifs, and showed Myc binding. Through the analysis of CREBBP mutations from a large cohort of primary human FL and DLBCL, we show a significant difference in the spectrum of CREBBP mutations in these 2 diseases, with higher frequencies of nonsense/ frameshift mutations in DLBCL compared with FL. Together, our data therefore provide important links between Crebbp inactivation and Bcl2 dependence and show a role for Crebbp inactivation in the induction of Myc expression. We suggest this may parallel the role of CREBBP frameshift/nonsense mutations in DLBCL that result in loss of the protein, but may contrast the role of missense mutations in the lysine acetyltransferase domain that are more frequently observed in FL and yield an inactive protein.

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Section: Discussioncontrasting

confidence: 90%

Crebbp loss cooperates with Bcl2 overexpression to promote lymphoma in mice

García-Ramírez

Tadros

González-Herrero

et al. 2017

Blood

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“…The role of BCL6 in ABC lymphomas remains largely unknown and it is possible that its alteration is required only for initiation of this lymphoma subtype (18), although recent reports indicate that activated B-cell lymphomas may require sustained BCL6 activity (19). As above, KMT2D and CREBBP are frequently mutated in follicular lymphoma and DLBCL and have also been implicated in B-cell maturation specifically via a reduction in CD40L and cytokine responsive transcription (8,9,20). The loss of chromatin modifiers in multiple lymphoma subtypes indicates that chromatin regulation may be critical at multiple points along the B-cell lineage.…”

Section: Introductionmentioning

confidence: 99%

EZH2 Inhibition by Tazemetostat Results in Altered Dependency on B-cell Activation Signaling in DLBCL

Brach

Johnston-Blackwell

Drew

et al. 2017

Molecular Cancer Therapeutics

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The EZH2 small-molecule inhibitor tazemetostat (EPZ-6438) is currently being evaluated in phase II clinical trials for the treatment of non-Hodgkin lymphoma (NHL). We have previously shown that EZH2 inhibitors display an antiproliferative effect in multiple preclinical models of NHL, and that models bearing gain-of-function mutations in EZH2 were consistently more sensitive to EZH2 inhibition than lymphomas with wild-type (WT) EZH2. Here, we demonstrate that cell lines bearing EZH2 mutations show a cytotoxic response, while cell lines with WT-EZH2 show a cytostatic response and only tumor growth inhibition without regression in a xenograft model. Previous work has demonstrated that cotreatment with tazemetostat and glucocorticoid receptor agonists lead to a synergistic antiproliferative effect in both mutant and wild-type backgrounds, which may provide clues to the mechanism of action of EZH2 inhibition in WT-EZH2 models. Multiple agents that inhibit the B-cell receptor pathway (e.g., ibrutinib) were found to have synergistic benefit when combined with tazemetostat in both mutant and WT-EZH2 backgrounds of diffuse large B-cell lymphomas (DLBCL). The relationship between B-cell activation and EZH2 inhibition is consistent with the proposed role of EZH2 in B-cell maturation. To further support this, we observe that cell lines treated with tazemetostat show an increase in the B-cell maturation regulator, PRDM1/BLIMP1, and gene signatures corresponding to more advanced stages of maturation. These findings suggest that EZH2 inhibition in both mutant and wild-type backgrounds leads to increased Bcell maturation and a greater dependence on B-cell activation signaling.

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“…Transitioning to the GC phenotype involves deep remodeling of the 3D architecture of the genome and extensive redistribution of epigenetic marks. Activation of BCL6 target genes in the light zone is mediated by the histone acetyltransferases CREBBP and EP300, and the histone methyltransferase KMT2D 88,95,103,104. 87,101 These genes are not "silenced," but instead are simply held in a poised configuration, where RNA Pol II is present and loaded at promoters but is not actively transcribing nascent mRNAs.…”

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confidence: 99%

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

Mlynarczyk

Fontán

Melnick

2019

Immunological Reviews

133

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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The CREBBP Acetyltransferase Is a Haploinsufficient Tumor Suppressor in B-cell Lymphoma

Cited by 194 publications

References 50 publications

Crebbp loss cooperates with Bcl2 overexpression to promote lymphoma in mice

Crebbp loss cooperates with Bcl2 overexpression to promote lymphoma in mice

EZH2 Inhibition by Tazemetostat Results in Altered Dependency on B-cell Activation Signaling in DLBCL

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

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