Abacavir, an anti–HIV-1 drug, targets TDP1-deficient adult T cell leukemia

Adult T cell leukemia (ATL) is an aggressive T cell malignancy caused by human T cell leukemia virus type 1 (HTLV-1) and has a poor prognosis. We analyzed the cytotoxic effects of various nucleoside analog reverse transcriptase inhibitors (NRTIs) for HIV-1 on ATL cells and found that abacavir potently and selectively kills ATL cells. Although NRTIs have minimal genotoxicities on host cells, the therapeutic concentration of abacavir induced numerous DNA double-strand breaks (DSBs) in the chromosomal DNA of ATL cells. DSBs persisted over time in ATL cells but not in other cell lines, suggesting impaired DNA repair. We found that the reduced expression of tyrosyl-DNA phosphodiesterase 1 (TDP1), a repair enzyme, is attributable to the cytotoxic effect of abacavir on ATL cells. We also showed that TDP1 removes abacavir from DNA ends in vitro. These results suggest a model in which ATL cells with reduced TDP1 expression are unable to excise abacavir incorporated into genomic DNA, leading to irreparable DSBs. On the basis of the above mechanism, we propose abacavir as a promising chemotherapeutic agent for ATL.

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

Life ◽

10.3390/life11020127 ◽

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.

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Long Noncoding RNA ANRIL Supports Proliferation of Adult T-Cell Leukemia Cells through Cooperation with EZH2

Journal of Virology ◽

10.1128/jvi.00909-18 ◽

2018 ◽

Vol 92 (24) ◽

Cited By ~ 5

Author(s):

Zaowen Song ◽

Wencai Wu ◽

Mengyun Chen ◽

Wenzhao Cheng ◽

Juntao Yu ◽

...

Keyword(s):

T Cell ◽

Long Noncoding Rna ◽

Noncoding Rna ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Cell Leukemia Virus Type ◽

Adult T Cell Leukemia ◽

Human T Cell

ABSTRACT Adult T-cell leukemia (ATL) is a highly aggressive T-cell malignancy induced by human T-cell leukemia virus type 1 (HTLV-1) infection. Long noncoding RNA (lncRNA) plays a critical role in the development and progression of multiple human cancers. However, the function of lncRNA in HTLV-1-induced oncogenesis has not been elucidated. In the present study, we show that the expression level of the lncRNA ANRIL was elevated in HTLV-1-infected cell lines and clinical ATL samples. E2F1 induced ANRIL transcription by enhancing its promoter activity. Knockdown of ANRIL in ATL cells repressed cellular proliferation and increased apoptosis in vitro and in vivo. As a mechanism for these actions, we found that ANRIL targeted EZH2 and activated the NF-κB pathway in ATL cells. This activation was independent of the histone methyltransferase (HMT) activity of EZH2 but required the formation of an ANRIL/EZH2/p65 ternary complex. A chromatin immunoprecipitation assay revealed that ANRIL/EZH2 enhanced p65 DNA binding capability. In addition, we observed that the ANRIL/EZH2 complex repressed p21/CDKN1A transcription through H3K27 trimethylation of the p21/CDKN1A promoter. Taken together, our results implicate that the lncRNA ANRIL, by cooperating with EZH2, supports the proliferation of HTLV-1-infected cells, which is thought to be critical for oncogenesis.IMPORTANCE Human T-cell leukemia virus type 1 (HTLV-1) is the pathogen that causes adult T-cell leukemia (ATL), which is a unique malignancy of CD4+ T cells. A role for long noncoding RNA (lncRNA) in HTLV-1-mediated cellular transformation has not been described. In this study, we demonstrated that the lncRNA ANRIL was important for maintaining the proliferation of ATL cells in vitro and in vivo. ANRIL was shown to activate NF-κB signaling through forming a ternary complex with EZH2 and p65. Furthermore, epigenetic inactivation of p21/CDKN1A was involved in the oncogenic function of ANRIL. To the best of our knowledge, this is the first study to address the regulatory role of the lncRNA ANRIL in ATL and provides an important clue to prevent or treat HTLV-1-associated human diseases.

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Long noncoding RNA ANRIL supports proliferation of adult T-cell leukemia cells through cooperation with EZH2

10.1101/329912 ◽

2018 ◽

Author(s):

Zaowen Song ◽

Wencai Wu ◽

Mengyun Chen ◽

Wenzhao Cheng ◽

Juntao Yu ◽

...

Keyword(s):

T Cell ◽

Long Noncoding Rna ◽

Noncoding Rna ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Cell Leukemia Virus Type ◽

Adult T Cell Leukemia ◽

Human T Cell

ABSTRACTAdult T-cell leukemia (ATL) is a highly aggressive T-cell malignancy induced by human T-cell leukemia virus type 1 (HTLV-1) infection. Long noncoding RNA (lncRNA) plays a critical role in the development and progression of multiple human cancers. However, the function of lncRNA on HTLV-1-induced oncogenesis has not been elucidated. In the present study, we show that the expression of the lncRNA ANRIL was elevated in HTLV-1 infected cell lines and clinical ATL samples. E2F1 induced ANRIL transcription by enhancing its promoter activity. Knocking down of ANRIL in ATL cells repressed cellular proliferation and increased apoptosis in vitro and in vivo. As a mechanism for these actions, we found that ANRIL targeted EZH2, and activated the NF-κB pathway in ATL cells. This activation was independent of the histone methyltransferase (HMT) activity of EZH2, but required the formation of an ANRIL/EZH2/p65 ternary complex. Chromatin immunoprecipitation assay revealed that ANRIL/EZH2 enhanced p65 DNA binding capability. In addition, we observed that ANRIL/EZH2 complex repressed p21/CDKN1A transcription through H3K27 trimethylation of the p21/CDKN1A promoter. Taken together, our results implicate that lncRNA ANRIL, by cooperating with EZH2, supports the proliferation of HTLV-1 infected cells, which is thought to be critical for oncogenesis.IMPORTANCEHuman T-cell leukemia virus type 1 (HTLV-1) is the pathogen that causes adult T-cell leukemia (ATL), which is a unique malignancy of CD4+ T cells. A role for long noncoding RNA (lncRNA) in HTLV-1-mediated cellular transformation has not been described. In this study, we demonstrated that lncRNA ANRIL was important for maintaining proliferation of ATL cells in vitro and in vivo. ANRIL was shown to activate NF-κB signaling through forming a ternary complex with EZH2 and p65. Further, epigenetic inactivation of p21/CDKN1A was involved in the oncogenic function of ANRIL. To the best of our knowledge, this is the first study to address the regulatory role of the lncRNA ANRIL in ATL and provides an important clue to prevent or treat HTLV-1 associated human diseases.

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T3 surface molecules on adult T cell leukemia cells are modulated in vivo

Blood ◽

10.1182/blood.v67.4.1070.bloodjournal6741070 ◽

1986 ◽

Vol 67 (4) ◽

pp. 1070-1076

Author(s):

M Matsuoka ◽

T Hattori ◽

T Chosa ◽

H Tsuda ◽

S Kuwata ◽

...

Keyword(s):

T Cell ◽

Type I ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Cell Leukemia Virus Type ◽

Adult T Cell Leukemia ◽

Receptor Complexes ◽

Human T Cell

Cells from eight patients with adult T cell leukemia (ATL) and from four patients with non-ATL were examined to see if the T3 antigen of these cells could be modulated in vitro. We found a low density of T3 antigen and the presence of Tac antigen on cells from all patients with ATL. The density of T3 antigen on non-ATL cells was normal, and Tac antigen was not detected. Modulation of T3 antigen and an increase in Tac antigen-positive cells occurred when cells from patients with T4 non-ATL were cultured with OKT3 monoclonal antibody (mAb). Those changes in T3 antigen density and the appearance of Tac antigen-bearing cells by OKT3 mAb were not so marked when ATL cells were used. But the modulation of T3 antigen and the increase in Tac antigen-bearing cells by OKT3 mAb were closely related in cells from six ATL patients. These findings suggest that T3 T cell antigen receptor complexes on ATL cells are not functionally “frozen” by leukemic changes and might be modulated in vivo. In addition, modulation of T3 surface antigen on ATL cells was not induced by cultivation with human T cell leukemia virus type I particles and envelope proteins obtained by gene technology.

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T3 surface molecules on adult T cell leukemia cells are modulated in vivo

Blood ◽

10.1182/blood.v67.4.1070.1070 ◽

1986 ◽

Vol 67 (4) ◽

pp. 1070-1076 ◽

Cited By ~ 33

Author(s):

M Matsuoka ◽

T Hattori ◽

T Chosa ◽

H Tsuda ◽

S Kuwata ◽

...

Keyword(s):

T Cell ◽

Type I ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Cell Leukemia Virus Type ◽

Adult T Cell Leukemia ◽

Receptor Complexes ◽

Human T Cell

Abstract Cells from eight patients with adult T cell leukemia (ATL) and from four patients with non-ATL were examined to see if the T3 antigen of these cells could be modulated in vitro. We found a low density of T3 antigen and the presence of Tac antigen on cells from all patients with ATL. The density of T3 antigen on non-ATL cells was normal, and Tac antigen was not detected. Modulation of T3 antigen and an increase in Tac antigen-positive cells occurred when cells from patients with T4 non-ATL were cultured with OKT3 monoclonal antibody (mAb). Those changes in T3 antigen density and the appearance of Tac antigen-bearing cells by OKT3 mAb were not so marked when ATL cells were used. But the modulation of T3 antigen and the increase in Tac antigen-bearing cells by OKT3 mAb were closely related in cells from six ATL patients. These findings suggest that T3 T cell antigen receptor complexes on ATL cells are not functionally “frozen” by leukemic changes and might be modulated in vivo. In addition, modulation of T3 surface antigen on ATL cells was not induced by cultivation with human T cell leukemia virus type I particles and envelope proteins obtained by gene technology.

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

Nature Communications ◽

10.1038/s41467-021-25101-9 ◽

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.

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

Molecular Cancer ◽

10.1186/s12943-021-01370-2 ◽

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.

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