The expansive reach of TET2

The gene encoding the methyl cytosine dioxygenase TET2 is often targeted by monoallelic or biallelic loss-of-function mutations and genomic alterations in myeloid malignancies. To investigate the role of TET2 directly, two papers report mouse models of Tet2 deficiency.

TET2 ... has pleiotropic effects on haematopoietic lineage commitment and the development of haematological malignancies

Moran-Crusio, Reavie, Shih and colleagues targeted exon 3 of Tet2 to generate a conditional knockout in the haematopoietic compartment (vav-cre;Tet2^f/f). They found that Tet2-deficient LIN⁻SCA1⁺KIT⁺ (LSK) progenitor cells were more able to undergo serial replating in colony-forming assays. The colonies that formed were poorly differentiated, had increased KIT expression levels and expressed a common myeloid progenitor (CMP) gene signature, indicating that loss of Tet2 impairs myeloid lineage commitment. Consistently, in vivo competition assays suggested that Tet2 loss increased the self-renewal of adult haematopoietic stem cells. Moreover, Tet2-deficient mice had increased populations of LSK and myeloid cells in the bone marrow, enlargement of the spleen and extramedullary haematopoiesis. Approximately 70% of Tet2-deficient mice developed phenotypes consistent with chronic myelomonocytic leukaemia (CMML). Interestingly, about 40% of patients with CMML have heterozygous TET2 mutations. To investigate the effect of heterozygous loss of Tet2, the authors repeated their analyses using vav-cre;Tet2^WT/f mice and found similar effects on haematopoiesis, indicating that Tet2 haploinsufficiency contributes to myeloid transformation.

Quivoron, Couronné, Della Valle and colleagues generated two Tet2-deficient mouse models (a conditional haematopoietic-specific knockout targeting exon 11 (Mx1-cre;Tet2^Lox/Loxmice) and a gene trap targeting intron 9 (Tet2^lacZ/lacZ mice)). Both homozygous and heterozygous loss of Tet2 in these mice resulted in expansion of the LSK cell, short- and long-term stem cell, myeloid cell and erythroid cell populations, which was associated with increased colony-forming potential. Also, homozygous and heterozygous Tet2 deficiency in the gene trap model caused the development with age of phenotypes consistent with CMML. LSK cells from either Tet2-deficient model reconstituted all haematopoietic lineages (including lymphoid lineages) in vivo, which indicates that Tet2 loss has a cell autonomous affect. Interestingly, these authors also found that CD4⁻CD8⁻ T cell progenitors were increased in the thymus and B cell lineages were decreased in the bone marrow, indicating that Tet2 loss also affects lymphoid lineage development. Indeed, the authors found TET2 mutations in human samples of B cell lymphoma (2%), T cell lymphoma (11.9%) and angioimmunoblastic T cell lymphoma (∼33%). The mutations were mainly heterozygous insertions and deletions that generated frameshifts and nonsense mutations. They also found genomic alterations targeting TET2 in T cell lymphoma samples, although, like myeloid malignancies, these were rare. Subsequent analyses of three TET2-mutant samples indicated that TET2 mutations were somatic rather than germline mutations. Deep exome sequencing of a T cell lymphoma sample revealed that mutations in cysteine-rich transmembrane BMP regulator 1 (CRIM1), zinc finger and BTB domain containing 16 (ZBTB16) and zinc finger protein 774 (ZNF774) occurred in addition to mutations in TET2. Other mutations, including those targeting the second TET2 allele, occurred at a later stage of lymphoma development.

Together, these papers indicate that TET2-mediated hydroxylation of methylcytosine is an important epigenetic modification, the loss of which has pleiotropic effects on haematopoietic lineage commitment and the development of haematological malignancies.