Tet2 at the interface between cancer and immunity

Abstract

Keeping a balance between DNA methylation and demethylation balance is central for mammalian development and cell function, particularly in the hematopoietic system. In various mammalian cells, Tet methylcytosine dioxygenase 2 (Tet2) catalyzes oxygen transfer to a methyl group of 5-methylcytosine (5mC), yielding 5-hydroxymethylcytocine (5hmC). Tet2 mutations drive tumorigenesis in several blood cancers as well as in solid cancers. Here I discuss recent studies that elucidate mechanisms and biological consequences of Tet2 dysregulation in blood cancers. I focus on recent findings concerning Tet2 involvement in lymphoid and myeloid cell development and its functional roles, which may be associated with tumorigenesis. I also discuss how Tet2 activities are modulated by microRNAs, metabolites, and other interactors, including vitamin C and 2-hydroxyglutarate (2-HG), and review the clinical relevance and potential therapeutic applications of Tet2 targeting. Finally, I propose key unanswered hypotheses regarding Tet2 in the cancer-immunity cycle.

Tet2 deficiency in immune cells exacerbates tumor progression by increasing angiogenesis in a lung cancer model

“…Loss of function TET2 mutations are found in a wide variety of blood cancers in addition to clonal hematopoiesis. 15 Deletion of Tet2 in the blood system resulted in myeloid cancer development after long latencies in mice, confirming its role as a tumor suppressor. 5 , 15 In solid cancers, previous analyses of melanoma 7 and liver cancer 8 models indicated that Tet2 ‐deficient MDSC modulate cancer progression by altering T cell‐mediated immunity, although they played opposite roles in T‐cell recruitment in each model.…”

“… 15 Deletion of Tet2 in the blood system resulted in myeloid cancer development after long latencies in mice, confirming its role as a tumor suppressor. 5 , 15 In solid cancers, previous analyses of melanoma 7 and liver cancer 8 models indicated that Tet2 ‐deficient MDSC modulate cancer progression by altering T cell‐mediated immunity, although they played opposite roles in T‐cell recruitment in each model. Intriguingly, our findings in a lung cancer model strongly suggest that Tet2 ‐deficient myeloid cells alter activity of a vascular niche for tumor cells rather than directly altering T‐cell mediated immunity.…”

“…TET2 protein plays roles in a variety of epigenetic regulations, such as the DNA demethylation process. 7 , 15 , 16 Tet2 deficiency has been reported to result in loss of hypermethylation, leading to a global change in gene expressions. It remains to be elucidated if upregulation of mediators in Tet2 ‐deficient immune cells in our studies is the direct effect of a dynamic change in DNA modification status.…”

Molecular Targeted Therapy and Immunotherapy for Myelodysplastic Syndrome

“…Moreover, loss-of-function mutation of TET2 results in a predominance of 5mC in DNA [ 134 ]. The accumulation of 5mC can promote B-cell development and function resulting in activation of innate immune systems, as well as the disruption of DNA methylation homeostasis [ 136 , 137 ]. Despite there being controversies in the functional impact of TET2 mutations in MDS, it remains as an important epigenetic enzyme [ 10 , 134 , 135 ].…”

Molecular Characterization of the Clinical and Tumor Immune Microenvironment Signature of 5-methylcytosine-Related Regulators in non-small Cell Lung Cancer

“…DNA 5mC methylation is the classic epigenetic process, which is controlled by “writers” (DNA methyltransferases), “erasers” (DNA methyltransferases), and “readers” ( Ito et al, 2011 ; Du et al, 2015 ; Lio et al, 2020 ). With the discovery of 5mC regulators, recent studies suggested that DNA cytosine modifications may act as epigenetic markers in tumorigenesis ( Wu and Zhang, 2010 ; Cavalcante et al, 2020 ; Jiang, 2020 ; Mo et al, 2020 ) and can regulate tumor microenvironment (TME) infiltrating cells ( Chen et al, 2020 ; Zhao et al, 2021 ; Onodera et al, 2021 ). However, the comprehensive roles of TME cell infiltration directed by 5mC regulators in NSCLC remain unclear.…”