Rapid isolation of viral integration site reveals frequent integration of HTLV-1 into expressed loci.
Although there is tight association of the human T-cell leukemia virus type-1 (HTLV-1) with adult T-cell leukemia/lymphoma (ATLL), it has remained unresolved whether the HTLV-1 integration into the host genome has any role in the development of this disease. We isolated a total of 58 HTLV-1 integration sites using newly developed, adaptor-ligated PCR from 33 ATLL patients and five ATLL cell lines. We compared our data as well as the previously reported ones with the complete human genomic sequence for the location of its placement, structure, and expression of genes nearby the integration site. The chromosomal target for integration was selected at random, but the integration favorably occurred within the transcription units; more than 59.5% of total integration was observed within the transcriptional unit. All inserted genes by HTLV-1 integration were expressed in normal T cells. Upregulation of genes due to viral integration was found in two out of nine ATLL cases; about 4.4- and 102-fold elevated ankyrin-1 ( ANK-1) and gephyrin ( GPHN) gene expressions were observed, respectively. These data suggest that the preferential integration of HTLV-1 into an expressed locus occasionally causes deregulation of corresponding gene, which may lead to leukemogenesis of a fraction of ATLL.
Ozawa
Tatsuhiko
T
Laboratory of Molecular and Cellular Biology, Department of Materials and Biosystem Engineering, Faculty of Engineering, Toyama University, 3190 Gofuku, Toyama 930-8555, Japan.
Itoyama
Takahiro
T
Laboratory of Molecular and Cellular Biology, Department of Materials and Biosystem Engineering, Faculty of Engineering, Toyama University, 3190 Gofuku, Toyama 930-8555, Japan.
Sadamori
Naoki
N
Department of Nursing, Siebold University of Nagasaki, Nagasaki 851-2195, Japan.
Yamada
Yasuaki
Y
Division of Laboratory Medicine, Department of Translational Medical Sciences, Nagasaki University Graduate School of Biomedical Sciences, 1-7-1 Sakamoto, Nagasaki 852-8501, Japan.
Hata
Tomoko
T
Department of Hematology, Molecular Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.
Tomonaga
Masao
M
Department of Hematology, Molecular Medicine Unit, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Biomedical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.
Isobe
Masaharu
M
Laboratory of Molecular and Cellular Biology, Department of Materials and Biosystem Engineering, Faculty of Engineering, Toyama University, 3190 Gofuku, Toyama 930-8555, Japan. isobe@eng.toyama-u.ac.jp.
D017487:Ankyrins / Q000096:biosynthesis; D002352:Carrier Proteins / Q000096:biosynthesis; D045744:Cell Line, Tumor; D002874:Chromosome Mapping; D019992:Databases as Topic; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D015490:HTLV-I Infections / Q000378:metabolism; D015368:Human T-lymphotropic virus 1 / Q000235:genetics*; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000821:virology*; D008565:Membrane Proteins / Q000096:biosynthesis; D016133:Polymerase Chain Reaction; D011533:Proviruses / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D015854:Up-Regulation; D016662:Virus Integration
C110202:ANK1 protein, human; D017487:Ankyrins; D002352:Carrier Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; C073441:gephyrin