title: Mutation analysis of mitotic checkpoint genes (hBUB1 and hBUBR1) and microsatellite instability in adult T-cell leukemia/lymphoma.
abstract: Adult T-cell leukemia/lymphoma (ATLL) is a neoplasm of T-lymphocytes, and human T-cell lymphotropic virus type-I (HTLV-I) is etiologically considered as the causative virus of ATLL. The karyotypes of ATLL are very complex in both number and structure, although no specific karyotype abnormalities have been identified. HTLV-I is thought to integrate its provirus into random sites in host chromosomal DNA and induces chromosomal instability. The BUB gene is a component of the mitotic checkpoint in budding yeast. Recently, human homologues of the BUB were identified and mutant alleles of hBUB1 and hBUBR1 were detected in two colorectal tumor cell lines, which showed microsatellite instability (MIN). In vitro, BUB proteins form a complex of monomers. These proteins interact with the human MAD1 gene product, a target of the HTLV-1 tax oncogene. We examined the role of checkpoint gene in the chromosomal abnormalities of ATLL by investigating mutations of hBUB1 and hBUBR1, and MIN of replication errors of BAX, insulin-like growth factor, and transforming growth factor beta type II. We analyzed ten cases with ATLL and eight B-cell lymphomas (five diffuse large cell lymphomas, three follicular lymphomas). Complex chromosomal abnormalities were detected in ATLL, while B-cell lymphomas showed only simple or minimal chromosomal abnormalities. Significant mutations/deletion of hBUB1 or hBUBR1 were detected in four of ten cases with ATLL, including two heterozygous point mutations, one homozygous point mutation, and one with a 47 bp deletion. In contrast, only one of eight B-cell lymphomas showed nonsense mutation of hBUBR1. None of the ATLL and B-cell lymphomas showed MIN. In the multistage process of leukemogenesis of ATLL, our findings indicate that mutations of mitotic checkpoint genes may play an important role in the induction of complex chromosomal abnormalities.
authors.affiliation: Department of Pathology, School of Medicine, Fukuoka University, Nanakuma 7-45-1, Jonan-ku, 814-01, Fukuoka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Ohshima
authors.forename: S
authors.initials: S
authors.lastname: Haraoka
authors.forename: S
authors.initials: S
authors.lastname: Yoshioka
authors.forename: M
authors.initials: M
authors.lastname: Hamasaki
authors.forename: T
authors.initials: T
authors.lastname: Fujiki
authors.forename: J
authors.initials: J
authors.lastname: Suzumiya
authors.forename: C
authors.initials: C
authors.lastname: Kawasaki
authors.forename: M
authors.initials: M
authors.lastname: Kanda
authors.forename: M
authors.initials: M
authors.lastname: Kikuchi
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D015703:Antigens, CD / Q000032:analysis; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics*; D002869:Chromosome Aberrations; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000737:chemistry / Q000235:genetics; D005838:Genotype; D015368:Human T-lymphotropic virus 1 / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018895:Microsatellite Repeats / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D017354:Point Mutation; D011494:Protein Kinases / Q000235:genetics; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2; D017527:Receptor, IGF Type 2 / Q000235:genetics; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D017384:Sequence Deletion; D051028:bcl-2-Associated X Protein
chemical_list: D015703:Antigens, CD; C494826:BAX protein, human; D018797:Cell Cycle Proteins; D018076:DNA, Complementary; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D017527:Receptor, IGF Type 2; D018125:Receptors, Transforming Growth Factor beta; D051028:bcl-2-Associated X Protein; D011494:Protein Kinases; C584277:BUB1 protein, human; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II