TY - JOUR
T1 - Crebbp loss cooperates with Bcl2 overexpression to promote lymphoma in mice
AU - García-Ramírez, Idoia
AU - Tadros, Saber
AU - González-Herrero, Inés
AU - Martín-Lorenzo, Alberto
AU - Rodríguez-Hernández, Guillermo
AU - Moore, Dalia
AU - Ruiz-Roca, Lucía
AU - Blanco, Oscar
AU - Alonso-López, Diego
AU - De Las Rivas, Javier
AU - Hartert, Keenan
AU - Duval, Romain
AU - Klinkebiel, David
AU - Bast, Martin
AU - Vose, Julie
AU - Lunning, Matthew
AU - Fu, Kai
AU - Greiner, Timothy
AU - Rodrigues-Lima, Fernando
AU - Jiménez, Rafael
AU - Criado, Francisco Javier García
AU - Cenador, María Begoña García
AU - Brindle, Paul
AU - Vicente-Dueñas, Carolina
AU - Alizadeh, Ash
AU - Sánchez-García, Isidro
AU - Green, Michael R.
N1 - Publisher Copyright:
© 2017 by The American Society of Hematology.
PY - 2017/5/11
Y1 - 2017/5/11
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2016-08-733469
DO - 10.1182/blood-2016-08-733469
M3 - Article
C2 - 28288979
AN - SCOPUS:85019669464
SN - 0006-4971
VL - 129
SP - 2645
EP - 2656
JO - Blood
JF - Blood
IS - 19
ER -