TET deficiency promotes oncogenesis and DNA damage in B cells by increasing the levels of G-quadruplexes and R-loops [HTGTS]

ABSTRACT: Enzymes of the TET family are methylcytosine dioxygenases that undergo frequent mutational or functional inactivation in both hematological and solid cancers. Recent studies have identified recurrent loss-of-function mutations in TET proteins in human patients with Diffuse Large B-Cell Lymphoma (DLBCL). Here we investigate the role of TET proteins in the pathogenesis of DLBCL by deleting the Tet2 and Tet3 genes in mature B cells in mice. Tet deletion perturbs mature B-cell homeostasis and causes spontaneous development of Germinal Center-derived B cell lymphomas. We show that an increase in G-quadruplexes and R-loops a common feature of TET deficiency in B cells as well as other hematopoietic cells. Genome-wide analyses revealed that G-quadruplexes and R-loops accumulated primarily near transcription start sites in TET-deficient B cells, and their accumulation correlated with increased DNA double-strand breaks. Moreover, CRISPR-mediated depletion of nucleases and helicases that regulate G-quadruplexes and R-loops led to decreased viability of TET-deficient but not control primary B cells. Our studies elucidate a molecular mechanism by which TET loss-of-function might predispose to development of B cell-derived and other malignancies, and highlight novel therapeutic avenues that could be further explored.

ORGANISM(S): Mus musculus

PROVIDER: GSE161461 | GEO | 2021/10/28

REPOSITORIES: GEO