Crebbp loss cooperates with Bcl2 overexpression to promote lymphoma in mice

Idoia García-Ramírez, Saber Tadros, Inés González-Herrero, Alberto Martín-Lorenzo, Guillermo Rodríguez-Hernández, Dalia Moore, Lucía Ruiz-Roca, Oscar Blanco, Diego Alonso-López, Javier De Las Rivas, Keenan Hartert, Romain Duval, David Klinkebiel, Martin Bast, Julie Vose, Matthew Lunning, Kai Fu, Timothy Greiner, Fernando Rodrigues-Lima, Rafael JiménezFrancisco Javier García Criado, María Begoña García Cenador, Paul Brindle, Carolina Vicente-Dueñas, Ash Alizadeh, Isidro Sánchez-García, Michael R. Green

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

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, andshowedMycbinding. Through the analysis ofCREBBPmutations 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.

Original languageEnglish (US)
Pages (from-to)2645-2656
Number of pages12
JournalBlood
Volume129
Issue number19
DOIs
StatePublished - May 11 2017

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Fingerprint

Dive into the research topics of 'Crebbp loss cooperates with Bcl2 overexpression to promote lymphoma in mice'. Together they form a unique fingerprint.

Cite this