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Nat Commun. 2018 Jan 15;9(1):222. doi: 10.1038/s41467-017-02595-w.

AICDA drives epigenetic heterogeneity and accelerates germinal center-derived lymphomagenesis.

Author information

1
Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, 10021, USA.
2
Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, 10021, USA.
3
Division of Biostatistics and Epidemiology, Weill Cornell Medicine, New York, NY, 10021, USA.
4
Centre for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC V5Z 4E6, Canada.
5
Department of Pathology, Laura and Isaac Perlmutter Cancer Center, and The Helen L. and Martin S. Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, NY, 10016, USA.
6
Division of Hematology, Department of Experimental Medicine and Oncology, University of Turin, 10124, Turin, Italy.
7
Immunology Program, Memorial Sloan-Kettering Cancer Center, Gerstner Sloan-Kettering Graduate School, New York, NY, 10021, USA.
8
Department of Pathology, British Columbia Cancer Agency, Vancouver, BC V5Z 4E6, Canada.
9
Pathology and Laboratory Medicine Department, Weill Cornell Medicine, New York, NY, 10021, USA.
10
Institute for Computational Biomedicine, Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY, 10021, USA. ole2001@med.cornell.edu.
11
Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, 10021, USA. ole2001@med.cornell.edu.
12
Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, 10021, USA. amm2014@med.cornell.edu.
13
Department of Medicine, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York, NY, 10021, USA. rshaknovich@gmail.com.
14
Cancer Genetics, Inc., Rutherford, NJ, 07070, USA. rshaknovich@gmail.com.

Abstract

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.

PMID:
29335468
PMCID:
PMC5768781
DOI:
10.1038/s41467-017-02595-w
[Indexed for MEDLINE]
Free PMC Article

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