title: Mutation of epigenetic regulators TET2 and MLL3 in patients with HTLV-I-induced acute adult T-cell leukemia.
abstract: BACKGROUND
  Epigenetic regulators play a critical role in the maintenance of specific chromatin domains in an active or repressed state. Disruption of epigenetic regulatory mechanisms is widespread in cancer cells and largely contributes to the transformation process through active repression of tumor suppressor genes. While mutations of epigenetic regulators have been reported in various lymphoid malignancies and solid cancers, mutation of these genes in HTLV-I-associated T-cell leukemia has not been investigated.
  
  
  METHODS
  Here we used whole genome next generation sequencing (NGS) of uncultured freshly isolated ATL samples and identified the presence of mutations in SUZ12, DNMT1, DNMT3A, DNMT3B, TET1, TET2, IDH1, IDH2, MLL, MLL2, MLL3 and MLL4.
  
  
  RESULTS
  TET2 was the most frequently mutated gene, occurring in 32 % (10/31) of ATL samples analyzed. Interestingly, NGS revealed nonsense mutations accompanied by loss of heterozygosity (LOH) in TET2 and MLL3, which was further confirmed by cloning and direct sequencing of DNA from uncultured cells. Finally, direct sequencing of matched control and tumor samples revealed that TET2 mutation was present only in ATL tumor cells.
  
  
  CONCLUSIONS
  Our results suggest that inactivation of MLL3 and TET2 may play an important role in the tumorigenesis process of HTLV-I-induced ATL.
authors.affiliation: Department of Pathology, Center for Viral Oncology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA.
authors.forename: Chien-Hung
authors.initials: CH
authors.lastname: Yeh
authors.affiliation: Department of Pathology, Center for Viral Oncology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA.
authors.forename: Xue Tao
authors.initials: XT
authors.lastname: Bai
authors.affiliation: Department of Pathology, Center for Viral Oncology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA.
authors.forename: Ramona
authors.initials: R
authors.lastname: Moles
authors.affiliation: Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, Saint Louis, MO, 63110, USA.
authors.forename: Lee
authors.initials: L
authors.lastname: Ratner
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Institutes of Health, Building 10, Room 4 N/115, 10 Center Drive, Bethesda, MD, 20892, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Waldmann
authors.affiliation: Department of Medical Genome Sciences, University of Tokyo, Tokyo, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Department of Medical Genome Sciences, University of Tokyo, Tokyo, Japan.
authors.forename: Watanabe
authors.initials: W
authors.lastname: Toshiki
authors.affiliation: Department of Pathology, Center for Viral Oncology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA. cnicot@kumc.edu.
authors.forename: Christophe
authors.initials: C
authors.lastname: Nicot
mesh_terms: D000328:Adult; D001483:Base Sequence; D002461:Cell Line, Transformed; D003001:Cloning, Molecular; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D049308:Dioxygenases; D044127:Epigenesis, Genetic; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics* / Q000821:virology*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012015:Reference Standards
chemical_list: D004268:DNA-Binding Proteins; C452979:KMT2C protein, human; D011518:Proto-Oncogene Proteins; D049308:Dioxygenases; C541081:TET2 protein, human