TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis.

By C. Quivoron, L. Couronné, V. Della Valle, Cécile K. Lopez, I. Plo, O. Wagner-Ballon, Marcio Do Cruzeiro, F. Delhommeau, B. Arnulf, M. Stern and 13 more. Cancer Cell, 2011

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Loss-of-function mutations affecting one or both copies of the Ten-Eleven-translocation (TET)2 gene have been described in various human myeloid malignancies. We report that inactivation of Tet2 in mouse perturbs both early and late steps of hematopoiesis including myeloid and lymphoid differentiation in a cell-autonomous manner, endows the cells with competitive advantage, and eventually leads to the development of malignancies. We subsequently observed TET2 mutations in human lymphoid disorders. TET2 mutations could be detected in immature progenitors endowed with myeloid colony-forming potential. Our results show that the mutations present in lymphoid tumor cells may occur at both early and later steps of lymphoid development and indicate that impairment of TET2 function or/and expression predisposes to the development of hematological malignancies.

Subfields: Hematology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/2f12e7fd79f4c2470957c436a5ea863d16928b0e

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DNA methylation dynamics during epigenetic reprogramming in the germline and preimplantation embryos (2014, background): “Tet1 and Tet2 are detected in ESCs and PGCs. Tet2 expression is essential in hematopoietic cells; knockouts are viable but develop severe, lethal hematopoietic malignancies at 4–6 mo of age (Li et al. 2011; Moran-Crusio et al. 2011; Quivoron et al. 2011; Koh and Rao 2013).”
Age-related clonal hematopoiesis associated with adverse outcomes. (2014, positive): “Although mutations in genes specific for lymphoid cancers were rarely detected, TET2 and DNMT3A are frequently mutated in some lymphoid cancers, and the initiating event for such tumors may occur in a hematopoietic stem cell.(24,39-42) This may explain why some of the cancers that developed in perso”
Epigenomic profiling of young and aged HSCs reveals concerted changes during aging that reinforce self-renewal (2014, background): “…leads to expansion of hematopoietic progenitors and increased stem cell self-renewal (Ko et al., 2011; Li et al., 2011; Moran-Crusio et al., 2011; Quivoron et al., 2011), and TET2 is recurrently mutated in myelodysplastic syndrome (MDS) and acute myeloid lymphoma (AML) patients (Delhommeau et…”
Cancer epigenetics: from mechanism to therapy. (2012, background): “Interestingly, TET2deficient mice develop a chronic myelomonocytic leukemia (CMML) phenotype, which is in keeping with the high prevalence of TET2 mutations in patients with this disease (Moran-Crusio et al., 2011; Quivoron et al., 2011).”
WT1 recruits TET2 to regulate its target gene expression and suppress leukemia cell proliferation (2015, positive): “in particular acute myeloid leukemia (AML, ~15 – 20%), and lymphoid lineages such as angioimmunoblastic T-cell lymphoma (AITL, ~30 – 40%) (Delhommeau et al., 2009; Quivoron et al., 2011; Tefferi et al., 2009).”
Reversing DNA Methylation: Mechanisms, Genomics, and Biological Functions (2014, positive): “Mouse genetic studies have demonstrated that Tet2-deficiency causes enhanced self-renew of hematopoietic stem cells (Ko et al., 2011; Li et al., 2011; Moran-Crusio et al., 2011; Quivoron et al., 2011), supporting a role of TET2 as tumor suppressor for leukemia.”