TET proteins and 5‐methylcytosine oxidation in hematological cancers

Abstract

Summary DNA methylation has pivotal regulatory roles in mammalian development, retrotransposon silencing, genomic imprinting and X-chromosome inactivation. Cancer cells display highly dysregulated DNA methylation profiles characterized by global hypomethylation in conjunction with hypermethylation of promoter CpG islands (CGIs) that presumably lead to genome instability and aberrant expression of tumor suppressor genes or oncogenes. The recent discovery of Ten-Eleven-Translocation (TET) family dioxygenases that oxidize 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) in DNA has led to profound progress in understanding the mechanism underlying DNA demethylation. Among the three TET genes, TET2 recurrently undergoes inactivating mutations in a wide range of myeloid and lymphoid malignancies. TET2 functions as a bona fide tumor suppressor particularly in the pathogenesis of myeloid malignancies resembling chronic myelomoncytic leukemia (CMML) and myelodysplastic syndromes (MDS) in human. Here we review diverse functions of TET proteins and the novel epigenetic marks that they generate in DNA methylation/demethylation dynamics and normal and malignant hematopoietic differentiation. The impact of TET2 inactivation in hematopoiesis and various mechanisms modulating the expression or activity of TET proteins are also discussed. Furthermore, we also present evidence that TET2 and TET3 collaborate to suppress aberrant hematopoiesis and hematopoietic transformation. A detailed understanding of the normal and pathological functions of TET proteins may provide new avenues to develop novel epigenetic therapies for treating hematological malignancies.

B-cell tumor development in Tet2-deficient mice

“…Besides underscoring nonredundant roles for ten-eleven translocation (TET) proteins in normal hematopoiesis and transformation, this reinforces a general function of TET(s) and DNA-methylation control as a tumor suppressor of B-cell malignancies. 13,44 A specific role of Tet3 in the B-cell lineage needs to be identified, however, because Tet3 inactivation does not markedly alter lymphopoiesis in mice (Ko et al 45 and our unpublished results).…”

Retinol and ascorbate drive erasure of epigenetic memory and enhance reprogramming to naïve pluripotency by complementary mechanisms

“…Moreover, the observation that RA signaling enhances TET2 expression could be relevant for the treatment of certain cancers. TET2 is a well-described tumor suppressor that is regularly mutated in a number of hematopoietic malignancies (46). Acute promyelocytic leukemia (APL) is a form of myeloid malignancy characterized by PML-RARα translocation and sensitivity to RA treatment, such that RA used in combination with arsenic trioxide can provide a 5-year event-free survival rate of >90% (47, 48), a dramatic improvement for what was once considered the deadliest form of acute leukemia.…”

Modulating Epigenetic Memory through Vitamins and TET: Implications for Regenerative Medicine and Cancer Treatment

“…Given that mutations in TET2 are well-known for their ability to suppress differentiation of myeloid lineages and drive malignancy [73,89], and TET2 is a direct target of the retinoic acid signaling pathway [37], it seems possible that instances of retinoic acid insensitivity in APL patients are due to TET2 mutation. Supporting this hypothesis is the finding that 4.5% of APL patients possess TET2 mutation, and along with disruption of several other epigenetic modifiers predicts poor treatment outcome [90].…”