Cargando…
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
BACKGROUND: 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...
Autores principales: | , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2017
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5282739/ https://www.ncbi.nlm.nih.gov/pubmed/28137248 http://dx.doi.org/10.1186/s12920-016-0241-2 |
_version_ | 1782503382537207808 |
---|---|
author | Farmanbar, Amir Firouzi, Sanaz Park, Sung-Joon Nakai, Kenta Uchimaru, Kaoru Watanabe, Toshiki |
author_facet | Farmanbar, Amir Firouzi, Sanaz Park, Sung-Joon Nakai, Kenta Uchimaru, Kaoru Watanabe, Toshiki |
author_sort | Farmanbar, Amir |
collection | PubMed |
description | BACKGROUND: 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. METHODS: As a comprehensively interdisciplinary project, this study combined three main aspects: wet laboratory experiments, in silico analysis and empirical modeling. RESULTS: 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. CONCLUSIONS: 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12920-016-0241-2) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5282739 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-52827392017-02-03 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 Farmanbar, Amir Firouzi, Sanaz Park, Sung-Joon Nakai, Kenta Uchimaru, Kaoru Watanabe, Toshiki BMC Med Genomics Research Article BACKGROUND: 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. METHODS: As a comprehensively interdisciplinary project, this study combined three main aspects: wet laboratory experiments, in silico analysis and empirical modeling. RESULTS: 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. CONCLUSIONS: 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. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12920-016-0241-2) contains supplementary material, which is available to authorized users. BioMed Central 2017-01-31 /pmc/articles/PMC5282739/ /pubmed/28137248 http://dx.doi.org/10.1186/s12920-016-0241-2 Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Farmanbar, Amir Firouzi, Sanaz Park, Sung-Joon Nakai, Kenta Uchimaru, Kaoru Watanabe, Toshiki 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 |
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 |
title_full | 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 |
title_fullStr | 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 |
title_full_unstemmed | 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 |
title_short | 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 |
title_sort | 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 |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5282739/ https://www.ncbi.nlm.nih.gov/pubmed/28137248 http://dx.doi.org/10.1186/s12920-016-0241-2 |
work_keys_str_mv | AT farmanbaramir multidisciplinaryinsightintoclonalexpansionofhtlv1infectedcellsinadulttcellleukemiaviamodelingbydeterministicfiniteautomatacoupledwithhighthroughputsequencing AT firouzisanaz multidisciplinaryinsightintoclonalexpansionofhtlv1infectedcellsinadulttcellleukemiaviamodelingbydeterministicfiniteautomatacoupledwithhighthroughputsequencing AT parksungjoon multidisciplinaryinsightintoclonalexpansionofhtlv1infectedcellsinadulttcellleukemiaviamodelingbydeterministicfiniteautomatacoupledwithhighthroughputsequencing AT nakaikenta multidisciplinaryinsightintoclonalexpansionofhtlv1infectedcellsinadulttcellleukemiaviamodelingbydeterministicfiniteautomatacoupledwithhighthroughputsequencing AT uchimarukaoru multidisciplinaryinsightintoclonalexpansionofhtlv1infectedcellsinadulttcellleukemiaviamodelingbydeterministicfiniteautomatacoupledwithhighthroughputsequencing AT watanabetoshiki multidisciplinaryinsightintoclonalexpansionofhtlv1infectedcellsinadulttcellleukemiaviamodelingbydeterministicfiniteautomatacoupledwithhighthroughputsequencing |