title: Transition of adult T-cell leukemia/lymphoma clones during clinical progression.
abstract: Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell neoplasm caused by the transformation of HTLV-1-infected T cells. ATLL, especially its aggressive form, is known for its poor prognosis, even with intensive chemotherapy. ATLL cells are considered to be monoclonal; however, multiclonal proliferation or emergence of a new clone over time has been reported based on Southern blot analysis, although direct molecular evidence remains elusive. Furthermore, it is thought that clonal change may be a cause of early drug resistance in ATLL. To directly analyze potential clonal changes in ATLL during its clinical course, we used inverse PCR to detect integration sites in combination with a newly developed method using next-generation sequencing, and compared ATLL cell clonality at different time points. The results of inverse PCR indicated that the major clone was altered in three of 19 patients. Together with results from five patients, using this new method, we found direct evidence of clonal change occurring during the clinical course or in response to chemotherapy in ATLL. These results also highlight the importance of clonality analysis for understanding the mechanisms of ATLL development and drug resistance.
authors.affiliation: Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Sakura
authors.initials: S
authors.lastname: Aoki
authors.affiliation: Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Sanaz
authors.initials: S
authors.lastname: Firouzi
authors.affiliation: Laboratory of Functional Analysis in Silico, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Yosvany
authors.initials: Y
authors.lastname: López
authors.affiliation: Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Tadanori
authors.initials: T
authors.lastname: Yamochi
authors.affiliation: Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Nakano
authors.affiliation: Hematology/Oncology, Research Hospital, the Institute of Medical Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Uchimaru
authors.affiliation: Department of Hematology, Imamura Bun-in Hospital, Kagoshima, Japan.
authors.forename: Atae
authors.initials: A
authors.lastname: Utusnomiya
authors.affiliation: Department of Frontier Life Science, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
authors.forename: Masako
authors.initials: M
authors.lastname: Iwanaga
authors.affiliation: Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan. tnabe@ims.u-tokyo.ac.jp.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Watanabe
mesh_terms: D000328:Adult; D002471:Cell Transformation, Neoplastic; D002999:Clone Cells / Q000473:pathology*; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000473:pathology*; D008875:Middle Aged; D016133:Polymerase Chain Reaction
keywords: Clonal change; Provirus integration site; Tag-NGS method