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

Nagasaka, Misako; Yamagishi, Masaaki; Yagishita, Naoko; Araya, Natsumi; Kobayashi, Seiichiro; Makiyama, Junya; Kubokawa, Miyuki; Yamauchi, Junji; Hasegawa, Daisuke; Coler‐Reilly, Ariella; Tsutsumi, Shuntaro; Uemura, Yu; Arai, Ayako; Takata, Ayako; Inoue, Eisuke; Hasegawa, Yasuhiro; Watanabe, Toshiki; Suzuki, Yutaka; Uchimaru, Kaoru; Sato, Tomoo; Yamano, Yoshihisa

doi:10.1073/pnas.1920346117

Cited by 34 publications

(41 citation statements)

References 36 publications

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“…Several such methods of analyzing transgene integration events using next generation sequencing (NGS) have recently been developed: namely, ligation-mediated PCR 10,11 , 86 target-capture sequencing 12,13 , LAM-PCR (linear amplification-mediated PCR) 14 , nrLAM-PCR (non-restrictive linear amplification-mediated PCR) 15,16 , and tag-PCR 17 . Some of these methods have already been employed in a clinical setting to assess the safety of retroviral and lentiviral gene therapies 14,15 .…”

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confidence: 99%

RAISING: a high-performance method for identifying random transgene integration sites

Wada¹,

Sato²,

Hasegawa³

et al. 2021

Preprint

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Both natural viral infections and therapeutic interventions using viral vectors pose significant risks of malignant transformation. Monitoring for clonal expansion of infected cells is important for detecting cancer. Here we developed a novel method of tracking transgene integration sites. RAISING (Rapid Amplification of Integration Sites without Interference by Genomic DNA contamination) is a sensitive, inexpensive alternative to established methods. Its compatibility with Sanger sequencing combined with our CLOVA (Clonality Value) software is critical for those without access to expensive next-generation sequencing. To model our method, we analyzed samples from 698 patients infected with the retrovirus HTLV-1, which causes adult T-cell leukemia/lymphoma (ATL). We defined a clonality value identifying ATL patients with 100% sensitivity and 95.3% specificity, and our preliminary longitudinal analysis suggests this may also be useful for ATL risk assessment. We anticipate future studies will confirm the broad applicability of our technology, especially in the emerging gene therapy sector.

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confidence: 99%

RAISING: a high-performance method for identifying random transgene integration sites

Wada¹,

Sato²,

Hasegawa³

et al. 2021

Preprint

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“…The ability to identify and predict which HTLV-I infected asymptomatic patients have a significantly higher risk to develop ATL will allow initiation of treatment earlier with greater improvement on patients’ overall survival. A recent study of TSP/HAM patients from Japan suggests that approximately 3% of TSP/HAM patients develop ATL [ 15 ]. We found approximately 7% of TSP/HAM patients carry a methylated FHIT allele.…”

Section: Discussionmentioning

confidence: 99%

“…Additional epigenetic or histone modifiers were also mutated; likely making these patients more susceptible to epigenetic treatment with DNA methyltransferase inhibitors. In a study focusing on TSP/HAM patient samples that progressed to ATL disease, those with a dominant clone and an ATL-like mutational signature went on to develop ATL [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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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“…HAM/TSP occurrence is generally associated with infection in adulthood through sexual transmission or blood transfusion. It is important to note that patients with juvenile HAM/TSP have been seen [62,63] and that ATLL is a major cause of death in HAM/TSP patients [64], suggesting that the transmission and pathogenesis of these two classes of HTLV-1 disease may not be entirely unrelated. Prior to onset of symptoms, clinical latency is typically anywhere from a couple of years to decades following infection (reviewed in [65,66]).…”

Section: The Clinical Spectrum Of Htlv-1 Infectionmentioning

confidence: 99%

Human T-cell Leukemia Virus Type 1 and Strongyloides stercoralis: Partners in Pathogenesis

et al. 2020

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Infection with human T-cell leukemia/lymphoma virus type 1 (HTLV-1) has been associated with various clinical syndromes including co-infection with Strongyloides stercoralis, which is an intestinal parasitic nematode and the leading cause of strongyloidiasis in humans. Interestingly, HTLV-1 endemic areas coincide with regions citing high prevalence of S. stercoralis infection, making these communities optimal for elucidating the pathogenesis of co-infection and its clinical significance. HTLV-1 co-infection with S. stercoralis has been observed for decades in a number of published patient cases and case series; however, the implications of this co-infection remain elusive. Thus far, data suggest that S. stercoralis increases proviral load in patients co-infected with HTLV-1 compared to HTLV-1 infection alone. Furthermore, co-infection with HTLV-1 has been associated with shifting the immune response from Th2 to Th1, affecting the ability of the immune system to address the helminth infection. Thus, despite this well-known association, further research is required to fully elucidate the impact of each pathogen on disease manifestations in co-infected patients. This review provides an analytical view of studies that have evaluated the variation within HTLV-1 patients in susceptibility to S. stercoralis infection, as well as the effects of strongyloidiasis on HTLV-1 pathogenesis. Further, it provides a compilation of available clinical reports on the epidemiology and pathology of HTLV-1 with parasitic co-infection as well as data from mechanistic studies suggesting possible immunopathogenic mechanisms. Furthermore, specific areas of potential future research have been highlighted to facilitate advancing understanding of the complex interactions between these two pathogens.

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

Cited by 34 publications

References 36 publications

RAISING: a high-performance method for identifying random transgene integration sites

RAISING: a high-performance method for identifying random transgene integration sites

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

Human T-cell Leukemia Virus Type 1 and Strongyloides stercoralis: Partners in Pathogenesis

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