HTLV-1 infection promotes excessive T cell activation and transformation into adult T cell leukemia/lymphoma

Tan, Benjy J.Y.; Sugata, Kenji; Reda, Omnia; Matsuo, Misaki; Uchiyama, Kyosuke; Miyazato, Paola; Hahaut, Vincent; Yamagishi, Masaaki; Uchimaru, Kaoru; Suzuki, Yutaka; Ueno, Takamasa; Suzushima, Hitoshi; Katsuya, Hiroo; Tokunaga, Masahito; Uchiyama, Yoshikazu; Nakamura, Hideaki; Sueoka, Eisaburo; Utsunomiya, Atae; Ono, Masahiro; Satou, Yorifumi

doi:10.1172/jci150472

Cited by 40 publications

(33 citation statements)

References 56 publications

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“…Jurkat-HBZ cells may thus represent a useful model to assess the role of HBZ in the progression of ATL. Future studies will be focused on the analysis of HBZ interactome in Jurkat-HBZ cells, as well as in additional ATL cell lines more closely mimicking the leukemic process ( 47 ) and in fresh leukemic cells ( 14 , 48 ) to further validate and possibly expand and compare proteomic data of HBZ interactors in other HTLV-1-derived ATL and in cells that are not derived from HTLV-1-induced leukaemia. Moreover, the analysis of the HBZ interactome in the cytoplasm of Jurkat-HBZ may unveil previously undetected HBZ-interacting partners which may explain the molecular correlates of cytoplasmic retention of the viral protein during the transition from non-malignant to malignant phenotype.…”

Section: Discussionmentioning

confidence: 99%

The endogenous HBZ interactome in ATL leukemic cells reveals an unprecedented complexity of host interacting partners involved in RNA splicing

et al. 2022

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Adult T-cell leukemia/lymphoma (ATL) is a T-cell lymphoproliferative neoplasm caused by the human T-cell leukemia virus type 1 (HTLV-1). Two viral proteins, Tax-1 and HBZ play important roles in HTLV-1 infectivity and in HTLV-1-associated pathologies by altering key pathways of cell homeostasis. However, the molecular mechanisms through which the two viral proteins, particularly HBZ, induce and/or sustain the oncogenic process are still largely elusive. Previous results suggested that HBZ interaction with nuclear factors may alter cell cycle and cell proliferation. To have a more complete picture of the HBZ interactions, we investigated in detail the endogenous HBZ interactome in leukemic cells by immunoprecipitating the HBZ-interacting complexes of ATL-2 leukemic cells, followed by tandem mass spectrometry analyses. RNA seq analysis was performed to decipher the differential gene expression and splicing modifications related to HTLV-1. Here we compared ATL-2 with MOLT-4, a non HTLV-1 derived leukemic T cell line and further compared with HBZ-induced modifications in an isogenic system composed by Jurkat T cells and stably HBZ transfected Jurkat derivatives. The endogenous HBZ interactome of ATL-2 cells identified 249 interactors covering three main clusters corresponding to protein families mainly involved in mRNA splicing, nonsense-mediated RNA decay (NMD) and JAK-STAT signaling pathway. Here we analyzed in detail the cluster involved in RNA splicing. RNAseq analysis showed that HBZ specifically altered the transcription of many genes, including crucial oncogenes, by affecting different splicing events. Consistently, the two RNA helicases, members of the RNA splicing family, DDX5 and its paralog DDX17, recently shown to be involved in alternative splicing of cellular genes after NF-κB activation by HTLV-1 Tax-1, interacted and partially co-localized with HBZ. For the first time, a complete picture of the endogenous HBZ interactome was elucidated. The wide interaction of HBZ with molecules involved in RNA splicing and the subsequent transcriptome alteration strongly suggests an unprecedented complex role of the viral oncogene in the establishment of the leukemic state.

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Section: Discussionmentioning

confidence: 99%

The endogenous HBZ interactome in ATL leukemic cells reveals an unprecedented complexity of host interacting partners involved in RNA splicing

et al. 2022

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“…Malignant T cells in ATL patients are derived from clonally expanded T cells with HTLV-1 provirus integrated into the cellular genome and express characteristic T cell markers, CD3 + , CD4 + , CD5 + , CD7 - , CD25 + , CD26 - , CCR4 + , CADM-1 + and monoclonal TCR Vβ ( 14 , 72 – 76 ). Using high throughput sequencing, TCR repertoire analysis in PBMCs demonstrated that ATL patients showed oligo- or monoclonal patterns of TCR clonotypes whereas asymptomatic carriers and healthy individuals showed polyclonal patterns ( 77 , 78 ). However, expression of TCR-α and TCR-β genes in the dominant clone differed among the samples ( 77 ).…”

Section: Tcr Repertoire Analysis In Atlmentioning

confidence: 99%

“…In ATL, four clinical subtypes (acute, lymphoma, chronic and smoldering) have been identified, which range from highly aggressive to indolent in their clinical course ( 11 ). Some studies have demonstrated significant variation in ATL TCR repertoire based on disease subtype in which smoldering ATL patients showed significantly higher TCR diversity compared with the other subtypes while diversity significantly decreased in more aggressive stages of the disease, including acute, chronic, and lymphoma types ( 77 , 78 ).…”

Section: Tcr Repertoire Analysis In Atlmentioning

confidence: 99%

T cell receptor repertoire analysis in HTLV-1-associated diseases

2022

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Human T lymphotropic virus 1 (HTLV-1) is a human retrovirus identified as the causative agent in adult T-cell leukemia/lymphoma (ATL) and chronic-progressive neuroinflammatory disorder HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 is estimated to infect between 5-20 million people worldwide, although most infected individuals remain asymptomatic. HTLV-1 infected persons carry an estimated lifetime risk of approximately 5% of developing ATL, and between 0.25% and 1.8% of developing HAM/TSP. Most HTLV-1 infection is detected in CD4+T cellsin vivowhich causes the aggressive malignancy in ATL. In HAM/TSP, the increase of HTLV-1 provirus induces immune dysregulation to alter inflammatory milieu, such as expansion of HTLV-1-specific CD8+T cells, in the central nervous system of the infected subjects, which have been suggested to underlie the pathogenesis of HAM/TSP. Factors contributing to the conversion from asymptomatic carrier to disease state remain poorly understood. As such, the identification and tracking of HTLV-1-specific T cell biomarkers that may be used to monitor the progression from primary infection to immune dysfunction and disease are of great interest. T cell receptor (TCR) repertoires have been extensively investigated as a mechanism of monitoring adaptive T cell immune response to viruses and tumors. Breakthrough technologies such as single-cell RNA sequencing have increased the specificity with which T cell clones may be characterized and continue to improve our understanding of TCR signatures in viral infection, cancer, and associated treatments. In HTLV-1-associated disease, sequencing of TCR repertoires has been used to reveal repertoire patterns, diversity, and clonal expansions of HTLV-1-specific T cells capable of immune evasion and dysregulation in ATL as well as in HAM/TSP. Conserved sequence analysis has further been used to identify CDR3 motif sequences and exploit disease- or patient-specificity and commonality in HTLV-1-associated disease. In this article we review current research on TCR repertoires and HTLV-1-specific clonotypes in HTLV-1-associated diseases ATL and HAM/TSP and discuss the implications of TCR clonal expansions on HTLV-1-associated disease course and treatments.

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“…EBV has been related to Burkitt lymphoma, DLBCL, nasal natural killer cell (NK) and T‐cell lymphomas 10‐13 . Adult T‐cell lymphoma is associated with infection by HTLV‐1 14 . HCV infection has been associated with B‐NHL subtypes as diffuse large B‐cell lymphoma, marginal zone lymphoma and lymphoplasmacytic lymphoma, 15,16 while H. pylori infection is a risk factor for gastric mucosa‐associated lymphoid tissue lymphoma 17 .…”

Section: Introductionmentioning

confidence: 99%

Global patterns of non‐Hodgkin lymphoma in 2020

Costa

Laversanne

Gospodarowicz

et al. 2022

Intl Journal of Cancer

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We evaluated the global patterns of non-Hodgkin lymphoma (NHL) in 2020 using the estimates of NHL incidence and mortality in 185 countries that are part of the GLO-BOCAN 2020 database, developed by the International Agency for Research on Cancer (IARC). As well as new cases and deaths of NHL, corresponding age-standardized (world) rates (ASR) of incidence and mortality per 100 000 person-years were derived by country and world region. In 2020, an estimated 544 000 new cases of NHL were diagnosed worldwide, and approximately 260 000 people died from the disease. Eastern Asia accounted for a quarter (24.9%) of all cases, followed by Northern America (15.1%) and South-Central Asia (9.7%). Incidence rates were higher in men than in women, with similar geographical patterns. While the incidence rates were highest in Australia and New Zealand, Northern America, Northern Europe and Western Europe (>10/100 000 for both sexes combined), the highest mortality rates (>3/100 000) were found in regions in Africa, Western Asia and Oceania. The large variations and the disproportionately higher mortality in low-and middle-income countries can be related to the underlying prevalence and distribution of risk factors, and to the level of access to diagnostic and treatment facilities.

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HTLV-1 infection promotes excessive T cell activation and transformation into adult T cell leukemia/lymphoma

Cited by 40 publications

References 56 publications

The endogenous HBZ interactome in ATL leukemic cells reveals an unprecedented complexity of host interacting partners involved in RNA splicing

The endogenous HBZ interactome in ATL leukemic cells reveals an unprecedented complexity of host interacting partners involved in RNA splicing

T cell receptor repertoire analysis in HTLV-1-associated diseases

Global patterns of non‐Hodgkin lymphoma in 2020

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