01 January 0001

Scientists have uncovered one way in which deficiency of TET enzymes leads to genomic instability and may pave the way for cancer. Enzymes in the TET family are often mutated or inactivated in cancer cells, including diffuse large B cell lymphoma.

A team led by Prof Anjana Rao of La Jolla Institute for Immunology, CA, USA, investigated the role of TET proteins in the development of such lymphomas in tests on mice. They found that deletion of the Tet2 and Tet3 genes in mature B cells upsets B cell homeostasis and leads to B cell lymphomas.

Co-lead author of the study Daniela Samaniego-Castruita said: “The TET-deficient mice developed lymphoma, and we observed an increase in marks associated with genomic instability, such as double strand breaks”.

While searching for the causes of this genomic instability, the team found that deleting Tet2 and Tet3 led to the formation of unusual DNA structures called R-loops and G-quadruplexes. “These structures represent sites in the DNA that are much more fragile than other regions,” said co-lead author Dr Vipul Shukla.

However, by altering levels of another enzyme which opposes the action of TET – called DNMT1 – the number of R-loops and G-quadruplexes were decreased. In turn, the deletion of DNMT1 in these TET-deficient mice delayed the development of lymphoma and improved survival.

“Our studies suggest a molecular mechanism by which TET loss of function might predispose to the development of B cell malignancies,” they write in the journal Nature Immunology.

Dr Shukla commented: “This study provides insights about an important question in the field.

“With this study, we found that TET enzymes are perhaps related to the regulation of these structures [R-loops and G-quadruplexes], which could in turn explain one mechanism for acquisition of genomic instability in the absence of TET enzymes.”



Shukla V, Samaniego-Castruita D, Dong Z, González-Avalos E, Yan Q, Sarma K, Rao A. (2021) “TET deficiency perturbs mature B cell homeostasis and promotes oncogenesis associated with accumulation of G-quadruplex and R-loop structures.” Nature Immunology, doi: 10.1038/s41590-021-01087-w

Link: https://www.nature.com/articles/s41590-021-01087-w

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