García-Ramírez Idoia, Tadros Saber, González-Herrero Inés, Martín-Lorenzo Alberto, Rodríguez-Hernández Guillermo, Moore Dalia, Ruiz-Roca Lucía, Blanco Oscar, Alonso-López Diego, Rivas Javier De Las, Hartert Keenan, Duval Romain, Klinkebiel David, Bast Martin, Vose Julie, Lunning Matthew, Fu Kai, Greiner Timothy, Rodrigues-Lima Fernando, Jiménez Rafael, Criado Francisco Javier García, Cenador María Begoña García, Brindle Paul, Vicente-Dueñas Carolina, Alizadeh Ash, Sánchez-García Isidro, Green Michael R
Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Cientificas/Universidad de Salamanca, Campus M. de Unamuno s/n, Salamanca, Spain.
Institute of Biomedical Research of Salamanca, Salamanca, Spain.
Blood. 2017 May 11;129(19):2645-2656. doi: 10.1182/blood-2016-08-733469. Epub 2017 Mar 13.
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.
CREBBP在滤泡性淋巴瘤（FL）和弥漫性大B细胞淋巴瘤（DLBCL）中因失活突变而成为靶点。在此，我们通过转基因小鼠模型提供证据表明，Crebbp缺失导致B细胞发育缺陷，并可与Bcl2过表达协同促进B细胞淋巴瘤。通过对这些B细胞进行转录和表观遗传分析，我们发现Crebbp失活与广泛的转录改变相关，但这些基因近端调控区域的组蛋白乙酰化模式没有变化。然而，Crebbp失活的B细胞显示Myc高表达，且组蛋白乙酰化模式改变，这些改变定位于基因内区域，富含Myc DNA结合基序，并显示有Myc结合。通过分析来自一大群原发性人类FL和DLBCL的CREBBP突变，我们发现这两种疾病中CREBBP突变谱存在显著差异，与FL相比，DLBCL中无义/移码突变的频率更高。因此，我们的数据共同提供了Crebbp失活与Bcl2依赖性之间的重要联系，并显示了Crebbp失活在诱导Myc表达中的作用。我们认为，这可能与DLBCL中导致蛋白质缺失的CREBBP移码/无义突变的作用相似，但可能与FL中更频繁观察到的赖氨酸乙酰转移酶结构域错义突变的作用相反，后者产生无活性蛋白质。
