Mutation analysis of mitotic checkpoint genes (hBUB1 and hBUBR1) and microsatellite instability in adult T-cell leukemia/lymphoma

Adult T-cell leukemia/lymphoma (ATLL) is a neoplasm of T-lymphocytes, and h uman 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 hav e 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, h uman homologues of the BUB were identified and mutant alleles of hBUB1 and hBUBR1 were detected in two colorectal tumor cell lines, which showed micro satellite instability (MIN). In vitro, BUB proteins form a complex of monom ers. 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 chr omosomal abnormalities of ATLL by investigating mutations of hBUB1 and hBUB R1, and MIN of replication errors of BAX, insulin-like growth factor. and t ransforming growth factor beta type II. We analyzed ten cases with ATLL and eight B-cell lymphomas (five diffuse large cell lymphomas, three follicula r lymphomas). Complex chromosomal abnormalities were detected in ATLL, whil e 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 homoz ygous 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 A TLL and B-cell lymphomas showed MIN. In the multistage process of leukemoge nesis of ATLL, our findings indicate that mutations of mitotic checkpoint g enes may play an important role in the induction of complex chromosomal abn ormalities. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.