Human TET2 bridges cancer and immunity

In this issue of Blood, Stremenova Spegarova et al report 3 patients with biallelic loss-of-function (LOF) TET2 mutations.(1) These patients suffered from infections, autoimmunity, and lymphoma, demonstrating 3 of the 5 potential phenotypes seen in inborn errors of immunity. TET2 encodes ten-eleven translocation methylcytosine dioxygenase 2 (TET2), 1 of the 3 members of the TET family of epigenetic regulators responsible for converting 5-methylcytosine to 5-hydroxymethylcytosine (5hmC) and subsequent oxidation products in an active DNA demethylation pathway. TET2 is ubiquitous, with particularly strong expression in hematopoietic cells. Somatic LOF TET2 mutations were first reported in patients with myeloproliferative disorders and hematologic cancers over 10 years ago.(2) TET2 haploinsufficiency has also recently been reported in families with myeloid or lymphoid cancers. Intriguingly, some of these patients also presented signs of enhanced monocyte- and macrophage-mediated inflammatory responses, together with atherosclerotic plaque development, which has been associated with increases in NLRP3 inflammasome activation.(3,4) Thus, the tumor suppressor role of TET2 has been extensively documented, especially in myeloid lineages.