Acute loss of TET function results in aggressive myeloid cancer in mice

An, Jeong Ho; González-Avalos, Edahí; Chawla, Ashu; Jeong, Mira; López-Moyado, Isaac F.; Li, Wei; Goodell, Margaret A.; Chávez, Lukas; Ko, Myunggon; Rao, Anjana

doi:10.1038/ncomms10071

Cited by 169 publications

(208 citation statements)

References 66 publications

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“…In contrast to TET1 KO mice, TET2/3 DKO mice develop AML within 2 months [8]. Gene expression analysis demonstrated deregulation of HR-and NHEJ-related genes in GMP and CD11b…”

Section: Repair Of Damaged Dna In Hscsmentioning

confidence: 99%

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Roles of IDH1/2 and TET2 mutations in myeloid disorders

2016

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Although mutated IDH1/2 are clearly established as oncogenes in myeloid cells, the mechanisms underlying their tumorigenic effects are not clear. Much evidence suggests that mutant IDH enzymes exert their effects via inhibition of TET2, but important clinical differences between IDH1-mutant and TET2-mutant hematopoietic disorders suggest that the oncogenic mechanisms of these mutated enzymes may differ. In particular, divergent effects of mutant IDH1/2 and TET2 on DNA damage repair mechanisms have been identified. In this review, we examine mutant IDH1/2 and TET2 in the context of responses to DNA damage and their potential involvement in genomic instability. We also discuss the clinical relevance of these findings and their potential application in novel therapeutic strategies. Mutation of TET family enzymesThe TET family of dioxygenases is highly conserved and contains three members: TET1, -2 and -3. Somatic mutations of TET2 occur in various myeloid disorders, including chronic myelomonocytic leukemia (CMML) (~50 %), myeloid proliferative neoplasm (MPN) (~13 %), MDS (~25 %) and AML (~23 %) [1,2]. TET2 is also mutated in B and T cell lymphoid malignancies, including angioimmunoblastic T cell lymphoma (AITL) [3]. More recently, TET2 mutations have been detected in elderly individuals with clonal hematopoiesis of indeterminate potential, i.e.: individuals with clonal hematopoiesis without identified hematological disease. This indicates that TET2 mutations alone cannot drive leukemogenesis and that additional events probably contribute [4,5]. Interestingly, TET1 and TET3 mutations are rare in human hematological diseases [6]. This predominance of TET2 alterations is not Abstract Mutations of the epigenetic enzymes isocitrate dehydrogenase (IDH) 1 and 2, and the methylcytosine dioxygenase 'ten-eleven translocation 2' (TET2), are common in human myeloid malignancies and drivers of these disorders but the underlying mechanisms remain obscure. This review examines mutant IDH1/2 and TET2 enzymes in the context of responses to DNA damage and their potential involvement in age-related genomic instability. The clinical relevance of these findings and their potential application in novel therapeutic strategies is also discussed.

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“…In contrast to TET1 KO mice, TET2/3 DKO mice develop AML within 2 months [8]. Gene expression analysis demonstrated deregulation of HR-and NHEJ-related genes in GMP and CD11b…”

Section: Repair Of Damaged Dna In Hscsmentioning

confidence: 99%

“…understood, particularly as conditional knockout (KO) of TET1, TET1/2 or TET2/3 in murine hematopoietic cells has profound biological consequences [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

Roles of IDH1/2 and TET2 mutations in myeloid disorders

2016

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“…The 5hmC marks are found at reduced levels (~1%) compared to the 5mC levels (4-5%) in the human genome. However, like 5mC alterations, the 5hmC patterns undergo considerable changes linked to genome instability (70,71) across several forms of human cancers (72). Recent studies revealed that 5hmC is consistently found at significantly reduced levels (more than 50% reduction, p ≤ 0.01) in various solid tumors (73)(74)(75).…”

Section: Dna Hydroxymethylationmentioning

confidence: 99%

Epigenetic regulation mechanisms of microRNA expression

Morales

Monzó

Navarro

2017

Biomolecular Concepts

121

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MicroRNAs (miRNAs) are single-stranded RNAs of 18-25 nucleotides that regulate gene expression at the post-transcriptional level. They are involved in many physiological and pathological processes, including cell proliferation, apoptosis, development and carcinogenesis. Because of the central role of miRNAs in the regulation of gene expression, their expression needs to be tightly controlled. Here, we summarize the different mechanisms of epigenetic regulation of miRNAs, with a particular focus on DNA methylation and histone modification.

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“…The role of TET proteins in malignant transformation has been reported in animal models (12,32). Removal of TET function induces the development of aggressive myeloid leukemia in a mouse model (32).…”

Section: Discussionmentioning

confidence: 99%

“…Removal of TET function induces the development of aggressive myeloid leukemia in a mouse model (32). TET1 expression is responsible for DNA methylation of tissue inhibitors of metalloproteinase proteins 2 and 3 (TIMP2, TIMP3) in prostate and breast cancer (19).…”

Section: Discussionmentioning

confidence: 99%

Transcript levels of ten-eleven translocation type 1–3 in cervical cancer and non-cancerous cervical tissues

et al. 2017

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Abstract. Decreased expression of ten-eleven translocation (TET1, TET2 and TET3) proteins has been reported in various types of cancer. However, the expression levels of TET proteins in cervical cancer (CC) remain to be elucidated. The present study determined the levels of TET1, TET2 and TET3 transcripts in cancerous (n=80) and non-cancerous cervical tissues (n=41). The results revealed a significant reduction in TET1 transcripts (P=0.0000001) in cervical tissue samples from patients with primary CC compared with samples from control patients. Significantly decreased TET1 transcript levels, as compared to non-cancerous cervical tissues, were also observed in tissue samples with the following characteristics: Stage I (P=0.016), II (P<0.0001), III (P=0.00007) and grade of differentiation G1 (P=0.026), G2 (P=0.00006), G3 (P=0.0007) and Gx (P=0.0004) and squamous histological type (P<0.00001). TET1 transcript levels were significantly lower in patients aged 45-60 years (P=0.0002) and patients age >60 years (P=0.003), as compared with non-cancerous cervical tissues. TET2 transcript levels were lower in cervical cancer tissues classified as stage II (P=0.043) and TET3 transcript levels were lower in stage III samples (P=0.010), tissue samples with a grade of differentiation of G3 (P=0.025) and tissue with squamous type histology (P=0.047), all compared with non-cancerous cervical tissues. The present study demonstrated a significantly reduced level of TET1 transcripts in cancerous cervical tissues, as compared with non-cancerous tissues. Furthermore, decreased TET1-3 transcript levels were identified when patients with CC were stratified by clinicopathological variables, as compared with non-cancerous cervical tissues.

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Acute loss of TET function results in aggressive myeloid cancer in mice

Cited by 169 publications

References 66 publications

Roles of IDH1/2 and TET2 mutations in myeloid disorders

Roles of IDH1/2 and TET2 mutations in myeloid disorders

Epigenetic regulation mechanisms of microRNA expression

Transcript levels of ten-eleven translocation type 1–3 in cervical cancer and non-cancerous cervical tissues

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