TET deficiency perturbs mature B cell homeostasis and promotes oncogenesis associated with accumulation of G-quadruplex and R-loop structures.

Autor: Shukla V; Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA, USA.; Department of Cell and Developmental Biology, Northwestern University, Chicago, IL, USA., Samaniego-Castruita D; Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA, USA.; Biological Sciences Graduate Program, University of California, San Diego, La Jolla, CA, USA., Dong Z; Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA, USA., González-Avalos E; Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA, USA.; Bioinformatics and Systems Biology Graduate Program, University of California, San Diego, La Jolla, CA, USA., Yan Q; Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA, USA.; Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA., Sarma K; Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA, USA.; Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA., Rao A; Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA, USA. arao@lji.org.; Department of Pharmacology and Moores Cancer Center, University of San Diego, La Jolla, CA, USA. arao@lji.org.; Sanford Consortium for Regenerative Medicine, La Jolla, CA, USA. arao@lji.org.
Jazyk: angličtina
Zdroj: Nature immunology [Nat Immunol] 2022 Jan; Vol. 23 (1), pp. 99-108. Date of Electronic Publication: 2021 Dec 22.
DOI: 10.1038/s41590-021-01087-w
Abstrakt: Enzymes of the TET family are methylcytosine dioxygenases that undergo frequent mutational or functional inactivation in human cancers. Recurrent loss-of-function mutations in TET proteins are frequent in human diffuse large B cell lymphoma (DLBCL). Here, we investigate the role of TET proteins in B cell homeostasis and development of B cell lymphomas with features of DLBCL. We show that deletion of Tet2 and Tet3 genes in mature B cells in mice perturbs B cell homeostasis and results in spontaneous development of germinal center (GC)-derived B cell lymphomas with increased G-quadruplexes and R-loops. At a genome-wide level, G-quadruplexes and R-loops were associated with increased DNA double-strand breaks (DSBs) at immunoglobulin switch regions. Deletion of the DNA methyltransferase DNMT1 in TET-deficient B cells prevented expansion of GC B cells, diminished the accumulation of G-quadruplexes and R-loops and delayed B lymphoma development, consistent with the opposing functions of DNMT and TET enzymes in DNA methylation and demethylation. Clustered regularly interspaced short palindromic repeats (CRISPR)-mediated depletion of nucleases and helicases that regulate G-quadruplexes and R-loops decreased the viability of TET-deficient B cells. Our studies suggest a molecular mechanism by which TET loss of function might predispose to the development of B cell malignancies.
(© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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