Transient expression of Bcl6 is sufficient for oncogenic function and induction of mature B-cell lymphoma

Green, Michael R.; Vicente-Dueñas, Carolina; Romero-Camarero, Isabel; Liu, Chih Long; Dai, Bo; González-Herrero, Inés; García-Ramírez, Idoia; Alonso-Escudero, Esther; Iqbal, Javeed; Chan, Wing C.; Campos-Sanchez, Elena; Órfão, Alberto; Pintado, Belén; Flores, Teresa; Blanco, Óscar; Jiménez, Rafael; Martínez-Climent, José A.; Criado, Francisco Javier García; Cenador, María Begoña García; Song, Zhao; Natkunam, Yasodha; Lossos, Izidore S.; Majeti, Ravindra; Melnick, Ari; Cobaleda, César; Alizadeh, Ash A.; Sánchez-Garcı́a, Isidro

doi:10.1038/ncomms4904

Cited by 76 publications

(77 citation statements)

References 69 publications

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“…In addition to GCB lymphomas, it has been shown that gain-of-function in BCL6 frequently occurs in ABC lymphomas (6), which display a more mature, post-germinal center phenotype. 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).…”

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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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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“…by guest www.bloodjournal.org From according to the manufacturer's instructions and analyzed as described previously. 27 For detailed methodology, refer to supplemental Methods. These data have been deposited in the Gene Expression Omnibus (GSE85490).…”

Section: Gene Expression Profilingmentioning

confidence: 99%

“…27 Briefly, samples were sectioned, dewaxed, and heated in 10 mmol/L sodium citrate buffer for 30 minutes. Slides were incubated with primary antibodies, including anti-MYC (Clone-Y69; Master Diagnostica, prediluted), anti-Bcl6 (Clone-LN22; Leica Biosystems), and anti-Pax5 (Clone-1EW, Leica Biosystems).…”

Section: Immunohistochemistry (Ihc)mentioning

confidence: 99%

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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“…[4][5][6] Furthermore, expression of several important proteins, such as BCL6, is also regulated by methylation status. 7,8 BCL6 is essential for GCB-cell development, as it is critical to cell proliferation, suppression of the DNA damage response during antibody class switching, and acquisition of somatic hypermutations. 9,10 A high level of BCL6 expression is consistently observed in GCB-DLBCL.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of demethylase KDM6B sensitizes diffuse large B-cell lymphoma to chemotherapeutic drugs

et al. 2016

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Transient expression of Bcl6 is sufficient for oncogenic function and induction of mature B-cell lymphoma

Cited by 76 publications

References 69 publications

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

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

Crebbp loss cooperates with Bcl2 overexpression to promote lymphoma in mice

Inhibition of demethylase KDM6B sensitizes diffuse large B-cell lymphoma to chemotherapeutic drugs

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