期刊
NATURE IMMUNOLOGY
卷 23, 期 1, 页码 99-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41590-021-01087-w
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资金
- NIH [NIH S10OD016262, NIH S10RR027366, DP2-NS105576, R35 CA210043, R01 AI109842, AI128589, K99/R00 CA248835]
- DOE Office of Science User Facility [DE-AC02-05CH11231]
- Shared Instrumentation Grant (SIG) Program (S10) [NovaSeq 6000 S10OD025052, HiSeq 2500 S10OD016262]
- Leukemia and Lymphoma Society Postdoctoral Fellowship [5463-18]
- K99/R00 award from the National Cancer Institute [CA248835]
- University of California Institute for Mexico
- University of California Institute for United States
- El Consejo Nacional de Ciencia y Tecnologia (UCMEXUS/CONACYT) pre-doctoral fellowship
- LLS [5463-18]
- LJI
Loss of TET methylcytosine dioxygenases in B cells is associated with increased DNA-RNA hybrids and G-quadruplex DNA structures, leading to genomic instability and the development of germinal center-derived lymphomas. Clustered regularly interspaced short palindromic repeats (CRISPR)-mediated depletion of nucleases and helicases that regulate G-quadruplexes and R-loops reduces the viability of TET-deficient B cells.
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. Shukla, Samaniego-Castruita and colleagues show that loss of TET methylcytosine dioxygenases in B cells is associated with increased DNA-RNA hybrids and G-quadruplex DNA structures in parallel with genomic instability and development of germinal center-derived lymphomas.
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