Clonality of HTLV-1–infected T cells as a risk indicator for development and progression of adult T-cell leukemia

Firouzi, Sanaz; Farmanbar, Amir; Nakai, Kenta; Iwanaga, Masako; Uchimaru, Kaoru; Utsunomiya, Atae; Suzuki, Yutaka; Watanabe, Toshiki

doi:10.1182/bloodadvances.2017005900

Cited by 36 publications

(29 citation statements)

References 35 publications

(37 reference statements)

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“…We then run the simulations on other available tools for IS identification such as VISPA [ 22 ], Mavric [ 16 ], SeqMap [ 14 ] and QuickMap [ 15 ] and we evaluated their performances (Table 1 , Additional file 2 ). VISPA2 showed a precision and recall of 1.0 and 0.97 respectively, a clear improvement with respect to VISPA [ 6 ], Mavric [ 9 ], and SeqMap [ 7 ] (Fig. 4 ).…”

Section: Resultsmentioning

confidence: 99%

VISPA2: a scalable pipeline for high-throughput identification and annotation of vector integration sites

et al. 2017

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BackgroundBioinformatics tools designed to identify lentiviral or retroviral vector insertion sites in the genome of host cells are used to address the safety and long-term efficacy of hematopoietic stem cell gene therapy applications and to study the clonal dynamics of hematopoietic reconstitution. The increasing number of gene therapy clinical trials combined with the increasing amount of Next Generation Sequencing data, aimed at identifying integration sites, require both highly accurate and efficient computational software able to correctly process “big data” in a reasonable computational time.ResultsHere we present VISPA2 (Vector Integration Site Parallel Analysis, version 2), the latest optimized computational pipeline for integration site identification and analysis with the following features: (1) the sequence analysis for the integration site processing is fully compliant with paired-end reads and includes a sequence quality filter before and after the alignment on the target genome; (2) an heuristic algorithm to reduce false positive integration sites at nucleotide level to reduce the impact of Polymerase Chain Reaction or trimming/alignment artifacts; (3) a classification and annotation module for integration sites; (4) a user friendly web interface as researcher front-end to perform integration site analyses without computational skills; (5) the time speedup of all steps through parallelization (Hadoop free).ConclusionsWe tested VISPA2 performances using simulated and real datasets of lentiviral vector integration sites, previously obtained from patients enrolled in a hematopoietic stem cell gene therapy clinical trial and compared the results with other preexisting tools for integration site analysis. On the computational side, VISPA2 showed a > 6-fold speedup and improved precision and recall metrics (1 and 0.97 respectively) compared to previously developed computational pipelines. These performances indicate that VISPA2 is a fast, reliable and user-friendly tool for integration site analysis, which allows gene therapy integration data to be handled in a cost and time effective fashion. Moreover, the web access of VISPA2 (http://openserver.itb.cnr.it/vispa/) ensures accessibility and ease of usage to researches of a complex analytical tool. We released the source code of VISPA2 in a public repository (https://bitbucket.org/andreacalabria/vispa2).Electronic supplementary materialThe online version of this article (doi:10.1186/s12859-017-1937-9) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

VISPA2: a scalable pipeline for high-throughput identification and annotation of vector integration sites

et al. 2017

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“…The clonality analysis of HTLV-1-infected T cells was also performed by high-throughput sequencing based mapping of proviral integration sites (15). To designate the virus integration site, the sequences spanning the viral and human genomes were identified and their junction points were extracted by as the soft-clipped read using the perl script and then validated by using Blastn, version 2.6.0+.…”

Section: Methodsmentioning

confidence: 99%

“…We thus asked whether patients with HAM/TSP are under increased risk of developing ATLL. Previous prospective studies demonstrated that peripheral blood HTLV-1 proviral load (PVL) at or more than 4% and clonal expansion of HTLV-1-infected cells reflect a high risk of ATLL transformation in HTLV-1 carriers (14,15). Although patients with HAM/TSP have increased HTLV-1 PVL compared with that of HTLV-1 carriers (16), whether or not they are at increased risk of developing ATLL has never been investigated.…”

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confidence: 99%

Mortality and risk of progression to adult T cell leukemia/lymphoma in HTLV-1–associated myelopathy/tropical spastic paraparesis

Nagasaka

Yamagishi

Yagishita

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Human T cell leukemia virus 1 (HTLV-1) causes the functionally debilitating disease HTLV-1–associated myelopathy/tropical spastic paraparesis (HAM/TSP) as well as adult T cell leukemia lymphoma (ATLL). Although there were concerns that the mortality of HAM/TSP could be affected by the development of ATLL, prospective evidence was lacking in this area. In this 5-y prospective cohort study, we determined the mortality, prevalence, and incidence of ATLL in 527 HAM/TSP patients. The standard mortality ratio of HAM/TSP patients was 2.25, and ATLL was one of the major causes of death (5/33 deaths). ATLL prevalence and incidence in these patients were 3.0% and 3.81 per 1,000 person-y, respectively. To identify patients at a high risk of developing ATLL, flow cytometry, Southern blotting, and targeted sequencing data were analyzed in a separate cohort of 218 HAM/TSP patients. In 17% of the HAM/TSP patients, we identified an increase in T cells positive for cell adhesion molecule 1 (CADM1), a marker for ATLL and HTLV-1–infected cells. Genomic analysis revealed that somatic mutations of HTLV-1–infected cells were seen in 90% of these cases and 11% of them had dominant clone and developed ATLL in the longitudinal observation. In this study, we were able to demonstrate the increased mortality in patients with HAM/TSP and a significant effect of ATLL on their prognosis. Having dominant clonal expansion of HTLV-1–infected cells with ATLL-associated somatic mutations may be important characteristics of patients with HAM/TSP who are at an increased risk of developing ATLL.

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“…Longitudinal monitoring of clonality among infected cells using HTLV-1 integration sites indicates that clonal expansion of infected cells occurs from the early stages of infection, even when individuals are still healthy and are diagnosed as asymptomatic carriers. Individuals with a largely expanded infected clone have a high risk of ATL development [37] , [38] . However, it is not clear whether the expanded cell populations are homogeneous or heterogeneous at a mutation level.…”

Section: Discussionmentioning

confidence: 99%

“…An analysis of the clonality pattern and the number of clones based on the provirus integration sites [34] indicates that the absolute abundance of infected and leukemic clones is a determining factor for ATL development [35] , [36] . High-throughput longitudinal analysis indicates that infected individuals with small clones and polyclonal patterns remain healthy over time, whereas those with large clones having an oligo- or monoclonal pattern develop ATL [37] , [38] . Also, recently a study on multi-organ clonality analysis in Simian T-Lymphotropic Virus type-1 associated leukemia- a simian counterpart of ATL- reported a complex clonality pattern in this disease [39] .…”

Section: Introductionmentioning

confidence: 99%

Mutational Intratumor Heterogeneity is a Complex and Early Event in the Development of Adult T-cell Leukemia/Lymphoma

Farmanbar

Firouzi

Makałowski³

et al. 2018

Neoplasia

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The clonal architecture of tumors plays a vital role in their pathogenesis and invasiveness; however, it is not yet clear how this clonality contributes to different malignancies. In this study we sought to address mutational intratumor heterogeneity (ITH) in adult T-cell leukemia/lymphoma (ATL). ATL is a malignancy with an incompletely understood molecular pathogenesis caused by infection with human T-cell leukemia virus type-1 (HTLV-1). To determine the clonal structure through tumor genetic diversity profiles, we investigated 142 whole-exome sequencing data of tumor and matched normal samples from 71 ATL patients. Based on SciClone analysis, the ATL samples showed a wide spectrum of modes over clonal/subclonal frequencies ranging from one to nine clusters. The average number of clusters was six across samples, but the number of clusters differed among different samples. Of these ATL samples, 94% had more than two clusters. Aggressive ATL cases had slightly more clonal clusters than indolent types, indicating the presence of ITH during earlier stages of disease. The known significantly mutated genes in ATL were frequently clustered together and possibly coexisted in the same clone. IRF4, CCR4, TP53, and PLCG1 mutations were almost clustered in subclones with a moderate variant allele frequency (VAF), whereas HLA-B, CARD11, and NOTCH1 mutations were clustered in subclones with lower VAFs. Taken together, these results show that ATL displays a high degree of ITH and a complex subclonal structure. Our findings suggest that clonal/subclonal architecture might be a useful measure for prognostic purposes and personalized assessment of the therapeutic response.

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Clonality of HTLV-1–infected T cells as a risk indicator for development and progression of adult T-cell leukemia

Abstract: Key Points• Oligo-or monoclonal expansion of HTLV-1-infected T cells in asymptomatic carriers predicts the onset of ATL.• Progression to acute type from indolent ATL was observed only in cases with monoclonal expansion.

Cited by 36 publications

References 35 publications

VISPA2: a scalable pipeline for high-throughput identification and annotation of vector integration sites

VISPA2: a scalable pipeline for high-throughput identification and annotation of vector integration sites

Mortality and risk of progression to adult T cell leukemia/lymphoma in HTLV-1–associated myelopathy/tropical spastic paraparesis

Mutational Intratumor Heterogeneity is a Complex and Early Event in the Development of Adult T-cell Leukemia/Lymphoma

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