TET2 Mutation in Adult T-Cell Leukemia/Lymphoma

Shimoda, Kazuya; Shide, Kotaro; Kameda, Takuro; Hidaka, Tomonori; Kubuki, Yoko; Kamiunten, Ayako; Sekine, Masaaki; Akizuki, Keiichi; Shimoda, Haruko; Yamaji, Takumi; Nakamura, Kenichi; Abe, Hiroo; Miike, Tadashi; Iwakiri, Hisayoshi; Tahara, Yoshihiro; Sueta, Mitsue; Yamamoto, Shojiro; Hasuike, Satoru; Nagata, Kenji; Kitanaka, Akira

doi:10.3960/jslrt.55.145

Cited by 18 publications

(19 citation statements)

References 26 publications

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“…Recent studies have reported the presence of TET2 mutations in ATLL patients from Japan [ 21 – 23 ]. However, whether TET2 mutations also exist in ATLL patients from other origins and whether they are specific for a clinical subtype of ATLL have not been investigated yet.…”

Section: Resultsmentioning

confidence: 99%

“…A simple explanation could be that reduced 5-hmc is due to TET2 mutations. Indeed, recent studies reported TET2 somatic mutations in ATLL patients from Japan (∼10% of patients) [ 21 – 23 ]. Our present data show on the one hand that TET2 mutations also exist in ATLL patients from African origin and on the other hand, that they are especially detected in the aggressive subtype.…”

Section: Discussionmentioning

confidence: 99%

“…TET2 and TET3 are expressed in CD4+ T lymphocytes while expression of TET1 is very low in these cells [ 15 ]. Mutations in the TET2 gene have been found in a variety of myeloid disorders and in mature lymphoid malignancies [ 16 – 20 ] and have also been recently described in Japanese ATLL patients [ 21 – 23 ]. In mice, TET2 inactivation induces expansion of hematopoietic progenitor cells and pleiotropic abnormalities affecting both myeloid and lymphoid lineages and Tet2 − / − mice develop diverse hematopoietic malignancies with long latency [ 24 – 26 ].…”

Section: Introductionmentioning

confidence: 99%

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Adult T cell leukemia aggressivenness correlates with loss of both 5-hydroxymethylcytosine and TET2 expression

et al. 2016

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Mutations in TET2, encoding one of the TET members responsible for the conversion of DNA cytosine methylation to hydroxymethylation (5-hmc), have been recently described in Human T-lymphotropic virus type 1-associated adult T-cell leukemia/lymphoma (ATLL). However, neither the amount of genomic 5-hmc in ATLL tumor cells nor TET2 expression has been studied yet. In this study, we analyzed these two parameters as well as the mutational status of TET2 in ATLL patients. By employing a direct in situ approach, we documented that tumor T cells infiltrating lymph nodes exhibit low level of 5-hmc compared to residual normal T cells. Furthermore, this 5-hmc defect was more pronounced in tumor T cells from acute patients than from chronic ones and correlated with reduced expression of TET2 protein. TET2 variations were found in 14 patients (20%), including 13 with aggressive forms. Strikingly, 9 of the 14 patients showed the same variation (SNP rs72963007), whose frequency in ATLL patients was significantly higher than that of an ethnically matched control population (13% vs. 5%). However, no reduction of 5-hmc was found in PBMC from individuals possessing the variant rs72963007 TET2 allele, as compared to wild-type individuals. In contrast, a robust correlation was observed between 5-hmc and the levels of TET2 mRNA. Finally, loss of 5-hmc and TET2 downregulation both correlated with poor survival. These findings demonstrate that ATLL progression coincides with loss of genomic 5-hmc and indicate that downregulation of TET2, rather than TET2 mutations, is the key mechanism involved in 5-hmc modulation during ATLL progression.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Adult T cell leukemia aggressivenness correlates with loss of both 5-hydroxymethylcytosine and TET2 expression

et al. 2016

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“…Finally, the accumulation of reactive oxygen species (ROS) results in DSBs in DNA . In addition, tax hinders DNA double‐strand break (DSB) repair factors and causes structural genomic abnormalities and aneuploidy . Tax disrupts SAC through the impact on the human homolog of MAD1, a vital component of the spindle checkpoint, which proceeds mitosis even though the correct attachment of sister chromatids to the mitotic spindle is impaired.…”

Section: Oncogenic Viruses and Their Role In Causing Aneuploidymentioning

confidence: 99%

Aneuploidy and oncoviruses

Taheri

Goudarzi

Faghihloo

2019

Reviews in Medical Virology

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Seven oncogenic viruses are known for tumorigenesis and contribute to 12% of all human cancers. The oncogenic factors, the target tissue, and pathology of cancer vary among these viruses with several mechanisms proposed for the initiation and development of cancer. Aneuploidy in cells is associated with anomalies in chromosome number that can be a hallmark of cancer, a disease defined by expanded proliferative potential. In this review, we summarize the different mechanisms of aneuploidy and furthermore discuss recent findings of the role of viral oncoproteins in inducing cellular aneuploidy that might facilitate tumorigenesis. Improved understanding of viral oncogenesis may help to find new strategies for controlling virus-associated cancers. KEYWORDS aneuploidy, cancer, virusThe key to precise segregation of chromosomes is that they should be correctly attached at the bipolar spindle, with sister kinetochore binding microtubules emanating from opposite spindle poles. Defects in kinetochore-microtubule (KT-MT) attachments in somatic cells cause segregation error and aneuploidy. [9][10][11] Abbreviations: KT-MT, kinetochore-microtubule; SAC, spindle assembly checkpoint; MCC, mitotic checkpoint complex; CPC, chromosomal passenger complex; BFB, breakage-fusionbridge; DSB, double-stranded break; HR, high risk; HCC, hepatocellular carcinoma; HBx, HBV X protein; LHBS, large surface antigen; AURKB, Aurora B kinase; LMP1, latent membrane protein 1; TK, thymidine kinase; HTLV-1, human T cell leukemia virus type 1;ATL, adult T cell leukemia/lymphoma; HBZ, basic leucine zipper factor; RanBP1, Ranspecific binding protein 1; NHEJ, nonhomologous end joining; ST, small tumor antigen;MEFs, mouse embryo fibroblasts

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“…Of these, TET2 was most frequently mutated in angioimmunoblastic T-cell lymphomas (up to 76%) and "Th follicular (TFH)−like" peripheral T-cell lymphomas (PTCL), not otherwise specified [10][11][12] (19-51%). TET2 mutation was also observed in approximately 10% of adult T cell leukemia/lymphoma cases 13,14 . As for B-cell malignancies, 0-12% of DLBCL patients were reported to carry TET2 mutation [15][16][17][18] .…”

Section: Introductionmentioning

confidence: 99%