scholarly journals Loss of interleukin-10 activates innate immunity to eradicate adult T cell leukemia initiating cells

Haematologica ◽  
2021 ◽  
Author(s):  
Hiba El Hajj ◽  
Rita Hleihel ◽  
Marwan El Sabban ◽  
Julie Bruneau ◽  
Ghazi Zaatari ◽  
...  
Keyword(s):  
Innate Immunity ◽  
T Cell ◽  
Cell Activity ◽  
Interleukin 10 ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Viral Oncoprotein ◽  
Cell Leukemia Virus Type ◽  
Adult T Cell Leukemia ◽  
Human T Cell

Adult T cell leukemia/lymphoma (ATL) is associated to chronic human T cell leukemia virus type 1 (HTLV-1) infection and carries a poor prognosis. Arsenic trioxide (AS) and interferon-alpha (IFNα) together selectively trigger Tax viral oncoprotein degradation and cure Tax-driven murine ATL. AS/IFNα/zidovudine treatment achieves a high response rate in patients with chronic ATL. Interleukin 10 (IL-10) is an immuno-suppressive cytokine whose expression is activated by Tax. Here we show that, in ATL, AS/IFNα-induced abrogation of leukemia initiating cell activity requires IL-10 expression shutoff. Loss of IL-10 secretion drives production of inflammatory cytokines by the microenvironment, followed by innate immunity-mediated clearance of Taxdriven leukemic cells. Accordingly, anti-IL-10 monoclonal antibodies significantly increased the efficiency of AS/IFNα therapy. These results emphasize the sequential targeting of malignant ATL cells and their immune microenvironment in leukemia initiating cell (LIC) eradication and provide a strong rational to test AS/IFNα/anti-IL10 combination in ATL.

scholarly journals Chronological genome and single-cell transcriptome integration characterizes the evolutionary process of adult T cell leukemia-lymphoma

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Makoto Yamagishi ◽  
Miyuki Kubokawa ◽  
Yuta Kuze ◽  
Ayako Suzuki ◽  
Akari Yokomizo ◽  
...  
Keyword(s):  
T Cell ◽  
Single Cell ◽  
Disease Onset ◽  
Evolutionary Process ◽  
Proliferative Potential ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Adult T Cell Leukemia ◽  
Human T Cell

AbstractSubclonal genetic heterogeneity and their diverse gene expression impose serious problems in understanding the behavior of cancers and contemplating therapeutic strategies. Here we develop and utilize a capture-based sequencing panel, which covers host hotspot genes and the full-length genome of human T-cell leukemia virus type-1 (HTLV-1), to investigate the clonal architecture of adult T-cell leukemia-lymphoma (ATL). For chronologically collected specimens from patients with ATL or pre-onset individuals, we integrate deep DNA sequencing and single-cell RNA sequencing to detect the somatic mutations and virus directly and characterize the transcriptional readouts in respective subclones. Characteristic genomic and transcriptomic patterns are associated with subclonal expansion and switches during the clinical timeline. Multistep mutations in the T-cell receptor (TCR), STAT3, and NOTCH pathways establish clone-specific transcriptomic abnormalities and further accelerate their proliferative potential to develop highly malignant clones, leading to disease onset and progression. Early detection and characterization of newly expanded subclones through the integrative analytical platform will be valuable for the development of an in-depth understanding of this disease.

scholarly journals Germinal epimutation of Fragile Histidine Triad (FHIT) gene is associated with progression to acute and chronic adult T-cell leukemia diseases

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Marcia Bellon ◽  
Izabela Bialuk ◽  
Veronica Galli ◽  
Xue-Tao Bai ◽  
Lourdes Farre ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Suppressor ◽  
Spastic Paraparesis ◽  
Cellular Transformation ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Fragile Histidine Triad ◽  
Adult T Cell Leukemia ◽  
Human T Cell

Abstract Background Human T cell Leukemia virus type 1 (HTLV-I) is etiologically linked to adult T cell leukemia/lymphoma (ATL) and an inflammatory neurodegenerative disease called HTLV-I-associated myelopathy or tropical spastic paraparesis (HAM/TSP). The exact genetic or epigenetic events and/or environmental factors that influence the development of ATL, or HAM/TSP diseases are largely unknown. The tumor suppressor gene, Fragile Histidine Triad Diadenosine Triphosphatase (FHIT), is frequently lost in cancer through epigenetic modifications and/or deletion. FHIT is a tumor suppressor acting as genome caretaker by regulating cellular DNA repair. Indeed, FHIT loss leads to replicative stress and accumulation of double DNA strand breaks. Therefore, loss of FHIT expression plays a key role in cellular transformation. Methods Here, we studied over 400 samples from HTLV-I-infected individuals with ATL, TSP/HAM, or asymptomatic carriers (AC) for FHIT loss and expression. We examined the epigenetic status of FHIT through methylation specific PCR and bisulfite sequencing; and correlated these results to FHIT expression in patient samples. Results We found that epigenetic alteration of FHIT is specifically found in chronic and acute ATL but is absent in asymptomatic HTLV-I carriers and TSP/HAM patients’ samples. Furthermore, the extent of FHIT methylation in ATL patients was quantitatively comparable in virus-infected and virus non-infected cells. We also found that longitudinal HTLV-I carriers that progressed to smoldering ATL and descendants of ATL patients harbor FHIT methylation. Conclusions These results suggest that germinal epigenetic mutation of FHIT represents a preexisting mark predisposing to the development of ATL diseases. These findings have important clinical implications as patients with acute ATL are rarely cured. Our study suggests an alternative strategy to the current “wait and see approach” in that early screening of HTLV-I-infected individuals for germinal epimutation of FHIT and early treatment may offer significant clinical benefits.

scholarly journals Biochemical Characterization, Specificity and Inhibition Studies of HTLV-1, HTLV-2, and HTLV-3 Proteases

Life ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 127
Author(s):  
Norbert Kassay ◽  
János András Mótyán ◽  
Krisztina Matúz ◽  
Mária Golda ◽  
József Tőzsér
Keyword(s):  
T Cell ◽  
Biochemical Characterization ◽  
Leukemia Virus ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Adult T Cell Leukemia ◽  
Human T Cell ◽  
T Cell Leukemia Virus

The human T-lymphotropic viruses (HTLVs) are causative agents of severe diseases including adult T-cell leukemia. Similar to human immunodeficiency viruses (HIVs), the viral protease (PR) plays a crucial role in the viral life-cycle via the processing of the viral polyproteins. Thus, it is a potential target of anti-retroviral therapies. In this study, we performed in vitro comparative analysis of human T-cell leukemia virus type 1, 2, and 3 (HTLV-1, -2, and -3) proteases. Amino acid preferences of S4 to S1′ subsites were studied by using a series of synthetic oligopeptide substrates representing the natural and modified cleavage site sequences of the proteases. Biochemical characteristics of the different PRs were also determined, including catalytic efficiencies and dependence of activity on pH, temperature, and ionic strength. We investigated the effects of different HIV-1 PR inhibitors (atazanavir, darunavir, DMP-323, indinavir, ritonavir, and saquinavir) on enzyme activities, and inhibitory potentials of IB-268 and IB-269 inhibitors that were previously designed against HTLV-1 PR. Comparative biochemical analysis of HTLV-1, -2, and -3 PRs may help understand the characteristic similarities and differences between these enzymes in order to estimate the potential of the appearance of drug-resistance against specific HTLV-1 PR inhibitors.

scholarly journals Smoking is a risk factor for development of adult T-cell leukemia/lymphoma in Japanese human T-cell leukemia virus type-1 carriers

2016 ◽  
Vol 27 (9) ◽  
pp. 1059-1066 ◽  
Author(s):  
Hisayoshi Kondo ◽  
Midori Soda ◽  
Norie Sawada ◽  
Manami Inoue ◽  
Yoshitaka Imaizumi ◽  
...  
Keyword(s):  
Risk Factor ◽  
T Cell ◽  
Leukemia Virus ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Adult T Cell Leukemia ◽  
Human T Cell ◽  
T Cell Leukemia Virus

The tumor marker Fascin is strongly induced by the Tax oncoprotein of HTLV-1 through NF-κB signals

Blood ◽  
2011 ◽  
Vol 117 (13) ◽  
pp. 3609-3612 ◽  
Author(s):  
Andrea K. Kress ◽  
Martina Kalmer ◽  
Aileen G. Rowan ◽  
Ralph Grassmann ◽  
Bernhard Fleckenstein
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Marker ◽  
Cd4 T Cells ◽  
Initial Step ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Viral Oncoprotein ◽  
Adult T Cell Leukemia ◽  
Human T Cell

AbstractOncogenic transformation of CD4+ T cells by human T-cell lymphotropic virus type 1 (HTLV-1) is understood as the initial step to adult T-cell leukemia/lymphoma, a process that is mainly initiated by perturbation of cellular signaling by the viral Tax oncoprotein, a potent transcriptional regulator. In search of novel biomarkers with relevance to oncogenesis, we identified the tumor marker and actin-bundling protein Fascin (FSCN1) to be specifically and strongly up-regulated in both HTLV-1–transformed and adult T-cell leukemia/lymphoma patient-derived CD4+ T cells. Fascin is important for migration and metastasis in various types of cancer. Here we report that a direct link can exist between a single viral oncoprotein and Fascin expression, as the viral oncoprotein Tax was sufficient to induce high levels of Fascin. Nuclear factor-κB signals were important for Tax-mediated transcriptional regulation of Fascin in T cells. This suggests that Fascin up-regulation by Tax contributes to the development of HTLV-1–associated pathogenesis.

Centrosome amplification in adult T-cell leukemia and human T-cell leukemia virus type 1 Tax-induced human T cells

2006 ◽  
Vol 97 (9) ◽  
pp. 836-841 ◽  
Author(s):  
Takayuki Nitta ◽  
Masayuki Kanai ◽  
Eiji Sugihara ◽  
Masakazu Tanaka ◽  
Binlian Sun ◽  
...  
Keyword(s):  
T Cell ◽  
Leukemia Virus ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Adult T Cell Leukemia ◽  
Human T Cell ◽  
Human T Cells ◽  
T Cell Leukemia Virus

scholarly journals Adult T-cell leukemia/lymphoma not associated with human T-cell leukemia virus type I.

1986 ◽  
Vol 83 (12) ◽  
pp. 4524-4528 ◽  
Author(s):  
M. Shimoyama ◽  
Y. Kagami ◽  
K. Shimotohno ◽  
M. Miwa ◽  
K. Minato ◽  
...  
Keyword(s):  
T Cell ◽  
Virus Type ◽  
Leukemia Virus ◽  
Type I ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Adult T Cell Leukemia ◽  
Human T Cell ◽  
T Cell Leukemia Virus

scholarly journals HTLV-1 infection of myeloid cells: from transmission to immune alterations

Retrovirology ◽  
2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Brenda Rocamonde ◽  
Auriane Carcone ◽  
Renaud Mahieux ◽  
Hélène Dutartre
Keyword(s):  
T Cell ◽  
Leukemia Virus ◽  
Spastic Paraparesis ◽  
Myeloid Cells ◽  
Cell Types ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Cell Leukemia Virus Type ◽  
Adult T Cell Leukemia ◽  
Human T Cell

AbstractHuman T cell leukemia virus type 1 (HTLV-1), the etiological agent of adult T-cell leukemia/lymphoma (ATLL) and the demyelinating neuroinflammatory disease known as HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP), was the first human retrovirus to be discovered. T-cells, which represent the main reservoir for HTLV-1, have been the main focus of studies aimed at understanding viral transmission and disease progression. However, other cell types such as myeloid cells are also target of HTLV-1 infection and display functional alterations as a consequence. In this work, we review the current investigations that shed light on infection, transmission and functional alterations subsequent to HTLV-1 infection of the different myeloid cells types, and we highlight the lack of knowledge in this regard.

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