TY - JOUR
T1 - AICDA drives epigenetic heterogeneity and accelerates germinal center-derived lymphomagenesis
AU - Teater, Matt
AU - Dominguez, Pilar M.
AU - Redmond, David
AU - Chen, Zhengming
AU - Ennishi, Daisuke
AU - Scott, David W.
AU - Cimmino, Luisa
AU - Ghione, Paola
AU - Chaudhuri, Jayanta
AU - Gascoyne, Randy D.
AU - Aifantis, Iannis
AU - Inghirami, Giorgio
AU - Elemento, Olivier
AU - Melnick, Ari
AU - Shaknovich, Rita
N1 - Funding Information:
We would like to thank T. Honjo (Kyoto University Graduate School of Medicine) for Aicda−/− mice, members of Melnick laboratory for useful discussions and suggestions, Epigenomics Core WCM, Genomics Resources Core Facility WCM, Flow Cytometry Core Facility WCM, Laboratory of Comparative Pathology WCMC and MSKCC. P.M.D. is supported by a Lymphoma Research Foundation Post-doctoral Fellowship. O.E. is supported by NSF CAREER, LLS SCOR, Hirschl Trust Award, Starr Cancer Consortium I6-A618, NIH 1R01CA19454. A.M. is supported by the Chemotherapy Foundation, Leukemia and Lymphoma Society SCOR Grant #7012-16 and the Starr Cancer Consortium.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Epigenetic heterogeneity is emerging as a feature of tumors. In diffuse large B-cell lymphoma (DLBCL), increased cytosine methylation heterogeneity is associated with poor clinical outcome, yet the underlying mechanisms remain unclear. Activation-induced cytidine deaminase (AICDA), an enzyme that mediates affinity maturation and facilitates DNA demethylation in germinal center (GC) B cells, is required for DLBCL pathogenesis and linked to inferior outcome. Here we show that AICDA overexpression causes more aggressive disease in BCL2-driven murine lymphomas. This phenotype is associated with increased cytosine methylation heterogeneity, but not with increased AICDA-mediated somatic mutation burden. Reciprocally, the cytosine methylation heterogeneity characteristic of normal GC B cells is lost upon AICDA depletion. These observations are relevant to human patients, since DLBCLs with high AICDA expression manifest increased methylation heterogeneity vs. AICDA-low DLBCLs. Our results identify AICDA as a driver of epigenetic heterogeneity in B-cell lymphomas with potential significance for other tumors with aberrant expression of cytidine deaminases.
AB - Epigenetic heterogeneity is emerging as a feature of tumors. In diffuse large B-cell lymphoma (DLBCL), increased cytosine methylation heterogeneity is associated with poor clinical outcome, yet the underlying mechanisms remain unclear. Activation-induced cytidine deaminase (AICDA), an enzyme that mediates affinity maturation and facilitates DNA demethylation in germinal center (GC) B cells, is required for DLBCL pathogenesis and linked to inferior outcome. Here we show that AICDA overexpression causes more aggressive disease in BCL2-driven murine lymphomas. This phenotype is associated with increased cytosine methylation heterogeneity, but not with increased AICDA-mediated somatic mutation burden. Reciprocally, the cytosine methylation heterogeneity characteristic of normal GC B cells is lost upon AICDA depletion. These observations are relevant to human patients, since DLBCLs with high AICDA expression manifest increased methylation heterogeneity vs. AICDA-low DLBCLs. Our results identify AICDA as a driver of epigenetic heterogeneity in B-cell lymphomas with potential significance for other tumors with aberrant expression of cytidine deaminases.
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U2 - 10.1038/s41467-017-02595-w
DO - 10.1038/s41467-017-02595-w
M3 - Article
C2 - 29335468
AN - SCOPUS:85040792130
SN - 2041-1723
VL - 9
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 222
ER -
