Successful Amplified-Natural-Killer Cell (ANK) Therapy Administered to a Patient with Smoldering Adult T-Cell Leukemia in Acute Crisis

Adult T-cell leukemia (ATL) is an indolent leukemia caused by type 1 human T-cell leukemia virus (HTLV-1). A variety of therapeutic interventions via immunological approaches have been attempted. ATL cells express costimulatory molecules of natural killer (NK) cells, and a new modality—amplified NK (ANK) cell treatment—was administered here to a patient with ATL. A 70-year-old female presenting with ringworm infection received a diagnosis of smoldering ATL in 2004. Monitoring of soluble IL-2 receptors (sIL-2Rs) in the serum showed disease exacerbation in 2007, associated with the enlargement of lymph nodes and formation of a skin tumor. NK cells were amplified by in vitro cell culture methods. To avoid cytokine release syndrome, 2–5 × 108 cells were administered with each injection. A total of 15 injections from 12 November 2007 to 15 February 2008 were administered to this patient. This case showed drastic downregulation of sIL-2R, resulting in the induction of complete remission, which lasted for >5 years. This is the first report of treatment of a patient with ATL using ANK cell therapy. More attempts of this therapy will enhance our insight into the appropriate application of this new therapy to clinically diverse patients.

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Seroreactivity to an Envelope Protein of Human T-Cell Leukemia/Lymphoma Virus in Patients With CD3− (Natural Killer) Lymphoproliferative Disease of Granular Lymphocytes

Blood ◽

10.1182/blood.v90.5.1977 ◽

1997 ◽

Vol 90 (5) ◽

pp. 1977-1981 ◽

Cited By ~ 40

Author(s):

Thomas P. Loughran ◽

Kenneth G. Hadlock ◽

Qing Yang ◽

Raisa Perzova ◽

Renato Zambello ◽

...

Keyword(s):

T Cell ◽

Nk Cells ◽

Natural Killer ◽

Lymphoproliferative Disorder ◽

Enzyme Linked Immunosorbent Assay ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Htlv Infection ◽

Human T Cell ◽

Granular Lymphocytes

Abstract Natural killer (NK) cells are CD3− large granular lymphocytes (LGL) responsible for immunity against viral infections. A chronic lymphoproliferative disorder of NK cells has been described in which the expanded NK cells display a restricted phenotype and cytotoxic activity. These data raise the hypothesis that proliferating LGL in these patients result from discrete expansions of NK cells responding to an unknown, perhaps viral, antigen. Recently, it was found that mice transgenic for the tax gene of human T-cell leukemia/lymphoma virus (HTLV) develop NK leukemia. Therefore, we studied 15 patients with chronic NK lymphoproliferative disorder for evidence of HTLV infection. Sera were tested using an HTLV-I/II-enzyme linked immunosorbent assay and a modified Western blot assay containing recombinant env proteins. None of the sera met conventional criteria for HTLV seroreactivity. However, sera from 11 patients (73%) reacted with the recombinant HTLV env protein p21E. The anti-p21E reactivity of these sera was then mapped employing the recombinant proteins GD21 and BA21. No reactivity to the immunodominant HTLV epitope GD21 was observed, suggesting that prototypical HTLV infection is unlikely in these patients. This was confirmed by finding no evidence for HTLV nucleic acids by PCR analyses employing primers specific for conserved regions in the env, pol, and pX genes. In contrast, 10 of the 15 sera reacted with the epitope BA21, documenting for the first time an association between a unique seroreactivity and disease. The high incidence of BA21 seroreactivity in these patients suggests that exposure to a protein containing homology to BA21 may be important in the pathogenesis of this lymphoproliferative disorder.

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

Cancer Causes & Control ◽

10.1007/s10552-016-0784-8 ◽

2016 ◽

Vol 27 (9) ◽

pp. 1059-1066 ◽

Cited By ~ 2

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

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The discovery of HTLV-1, the first pathogenic human retrovirus

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1521629112 ◽

2015 ◽

Vol 112 (51) ◽

pp. 15525-15529 ◽

Cited By ~ 16

Author(s):

John M. Coffin

Keyword(s):

T Cell ◽

Human Cancer ◽

Leukemia Virus ◽

Conclusive Evidence ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Culture Methods ◽

Research Knowledge ◽

Adult T Cell Leukemia ◽

Human T Cell

After the discovery of retroviral reverse transcriptase in 1970, there was a flurry of activity, sparked by the “War on Cancer,” to identify human cancer retroviruses. After many false claims resulting from various artifacts, most scientists abandoned the search, but the Gallo laboratory carried on, developing both specific assays and new cell culture methods that enabled them to report, in the accompanying 1980 PNAS paper, identification and partial characterization of human T-cell leukemia virus (HTLV; now known as HTLV-1) produced by a T-cell line from a lymphoma patient. Follow-up studies, including collaboration with the group that first identified a cluster of adult T-cell leukemia (ATL) cases in Japan, provided conclusive evidence that HTLV was the cause of this disease. HTLV-1 is now known to infect at least 4–10 million people worldwide, about 5% of whom will develop ATL. Despite intensive research, knowledge of the viral etiology has not led to improvement in treatment or outcome of ATL. However, the technology for discovery of HTLV and acknowledgment of the existence of pathogenic human retroviruses laid the technical and intellectual foundation for the discovery of the cause of AIDS soon afterward. Without this advance, our ability to diagnose and treat HIV infection most likely would have been long delayed.

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Human T-cell lymphotropic virus type I (HTLV-I) antibodies in pre-diagnostic serum of patients with familial adult T-cell leukemia/lymphoma (ATL)

Hematological Oncology ◽

10.1002/hon.2900080308 ◽

2006 ◽

Vol 8 (3) ◽

pp. 169-176 ◽

Cited By ~ 1

Author(s):

Abraham M. Y. Nomura ◽

Eugene T. Yanagihara ◽

William A. Blattner ◽

Gloria Y. F. Ho ◽

Melvin S. Inamasu ◽

...

Keyword(s):

T Cell ◽

Virus Type ◽

Type I ◽

T Cell Leukemia ◽

Cell Leukemia ◽

Adult T Cell Leukemia ◽

Human T Cell

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

Blood ◽

10.1182/blood-2010-09-305805 ◽

2011 ◽

Vol 117 (13) ◽

pp. 3609-3612 ◽

Cited By ~ 22

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.

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