title: Multidisciplinary insight into clonal expansion of HTLV-1-infected cells in adult T-cell leukemia via modeling by deterministic finite automata coupled with high-throughput sequencing.
abstract: Clonal expansion of leukemic cells leads to onset of adult T-cell leukemia (ATL), an aggressive lymphoid malignancy with a very poor prognosis. Infection with human T-cell leukemia virus type-1 (HTLV-1) is the direct cause of ATL onset, and integration of HTLV-1 into the human genome is essential for clonal expansion of leukemic cells. Therefore, monitoring clonal expansion of HTLV-1-infected cells via isolation of integration sites assists in analyzing infected individuals from early infection to the final stage of ATL development. However, because of the complex nature of clonal expansion, the underlying mechanisms have yet to be clarified. Combining computational/mathematical modeling with experimental and clinical data of integration site-based clonality analysis derived from next generation sequencing technologies provides an appropriate strategy to achieve a better understanding of ATL development.
  
  
  
  As a comprehensively interdisciplinary project, this study combined three main aspects: wet laboratory experiments, in silico analysis and empirical modeling.
  
  
  
  We analyzed clinical samples from HTLV-1-infected individuals with a broad range of proviral loads using a high-throughput methodology that enables isolation of HTLV-1 integration sites and accurate measurement of the size of infected clones. We categorized clones into four size groups, "very small", "small", "big", and "very big", based on the patterns of clonal growth and observed clone sizes. We propose an empirical formal model based on deterministic finite state automata (DFA) analysis of real clinical samples to illustrate patterns of clonal expansion.
  
  
  
  Through the developed model, we have translated biological data of clonal expansion into the formal language of mathematics and represented the observed clonality data with DFA. Our data suggest that combining experimental data (absolute size of clones) with DFA can describe the clonality status of patients. This kind of modeling provides a basic understanding as well as a unique perspective for clarifying the mechanisms of clonal expansion in ATL.
authors.affiliation: Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.|Laboratory of Functional Analysis in silico, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Amir
authors.initials: A
authors.lastname: Farmanbar
authors.affiliation: Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan. firouzisanaz1@gmail.com.
authors.forename: Sanaz
authors.initials: S
authors.lastname: Firouzi
authors.affiliation: Laboratory of Functional Analysis in silico, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Sung-Joon
authors.initials: SJ
authors.lastname: Park
authors.affiliation: Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.|Laboratory of Functional Analysis in silico, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Nakai
authors.affiliation: Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.|Hematology/Oncology, Research Hospital, Institute of Medical Sciences, The University of Tokyo, Tokyo, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Uchimaru
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.|Department of Advanced Medical Innovation, St. Marianna University School of Medicine, Kanagawa, Japan. tnabe@ims.u-tokyo.ac.jp.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Watanabe
mesh_terms: D000328:Adult; D049109:Cell Proliferation; D059014:High-Throughput Nucleotide Sequencing; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics / Q000473:pathology* / Q000821:virology*; D008954:Models, Biological
keywords: Adult T-cell leukemia; Clonal expansion; Deterministic finite state automata (DFA); Human T-cell leukemia virus ype-1; Integration site; Mathematical computational modeling; Next-generation sequencing; State-transition diagram