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

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 environme...

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Autores: Bellon, Marcia, Bialuk, Izabela, Galli, Veronica, Bai, Xue-Tao, Farré, Lourdes, Bittencourt, Achilea, Marçais, Ambroise, Petrus, Michael N., Ratner, Lee, Waldmann, Thomas A., Asnafi, Vahid, Gessain, Antoine, Matsuoka, Masao, Franchini, Genoveffa, Hermine, Olivier, Watanabe, Toshiki, Nicot, Christophe
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/178671
Acceso en línea:https://hdl.handle.net/2445/178671
Access Level:acceso abierto
Palabra clave:Leucèmia
Epigenètica
Càncer
Leukemia
Epigenetics
Cancer
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spelling Germinal epimutation of Fragile Histidine Triad (FHIT) gene is associated with progression to acute and chronic adult T-cell leukemia diseasesBellon, MarciaBialuk, IzabelaGalli, VeronicaBai, Xue-TaoFarré, LourdesBittencourt, AchileaMarçais, AmbroisePetrus, Michael N.Ratner, LeeWaldmann, Thomas A.Asnafi, VahidGessain, AntoineMatsuoka, MasaoFranchini, GenoveffaHermine, OlivierWatanabe, ToshikiNicot, ChristopheLeucèmiaEpigenèticaCàncerLeukemiaEpigeneticsCancerBackground: 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.Springer Nature2021202120212021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion15 p.application/pdfhttps://hdl.handle.net/2445/178671Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.1186/s12943-021-01370-2Molecular Cancer, 2021, vol. 20https://doi.org/10.1186/s12943-021-01370-2cc by (c) Bellon et al., 2021http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1786712026-05-29T05:05:01Z
dc.title.none.fl_str_mv Germinal epimutation of Fragile Histidine Triad (FHIT) gene is associated with progression to acute and chronic adult T-cell leukemia diseases
title Germinal epimutation of Fragile Histidine Triad (FHIT) gene is associated with progression to acute and chronic adult T-cell leukemia diseases
spellingShingle Germinal epimutation of Fragile Histidine Triad (FHIT) gene is associated with progression to acute and chronic adult T-cell leukemia diseases
Bellon, Marcia
Leucèmia
Epigenètica
Càncer
Leukemia
Epigenetics
Cancer
title_short Germinal epimutation of Fragile Histidine Triad (FHIT) gene is associated with progression to acute and chronic adult T-cell leukemia diseases
title_full Germinal epimutation of Fragile Histidine Triad (FHIT) gene is associated with progression to acute and chronic adult T-cell leukemia diseases
title_fullStr Germinal epimutation of Fragile Histidine Triad (FHIT) gene is associated with progression to acute and chronic adult T-cell leukemia diseases
title_full_unstemmed Germinal epimutation of Fragile Histidine Triad (FHIT) gene is associated with progression to acute and chronic adult T-cell leukemia diseases
title_sort Germinal epimutation of Fragile Histidine Triad (FHIT) gene is associated with progression to acute and chronic adult T-cell leukemia diseases
dc.creator.none.fl_str_mv Bellon, Marcia
Bialuk, Izabela
Galli, Veronica
Bai, Xue-Tao
Farré, Lourdes
Bittencourt, Achilea
Marçais, Ambroise
Petrus, Michael N.
Ratner, Lee
Waldmann, Thomas A.
Asnafi, Vahid
Gessain, Antoine
Matsuoka, Masao
Franchini, Genoveffa
Hermine, Olivier
Watanabe, Toshiki
Nicot, Christophe
author Bellon, Marcia
author_facet Bellon, Marcia
Bialuk, Izabela
Galli, Veronica
Bai, Xue-Tao
Farré, Lourdes
Bittencourt, Achilea
Marçais, Ambroise
Petrus, Michael N.
Ratner, Lee
Waldmann, Thomas A.
Asnafi, Vahid
Gessain, Antoine
Matsuoka, Masao
Franchini, Genoveffa
Hermine, Olivier
Watanabe, Toshiki
Nicot, Christophe
author_role author
author2 Bialuk, Izabela
Galli, Veronica
Bai, Xue-Tao
Farré, Lourdes
Bittencourt, Achilea
Marçais, Ambroise
Petrus, Michael N.
Ratner, Lee
Waldmann, Thomas A.
Asnafi, Vahid
Gessain, Antoine
Matsuoka, Masao
Franchini, Genoveffa
Hermine, Olivier
Watanabe, Toshiki
Nicot, Christophe
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Leucèmia
Epigenètica
Càncer
Leukemia
Epigenetics
Cancer
topic Leucèmia
Epigenètica
Càncer
Leukemia
Epigenetics
Cancer
description 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.
publishDate 2021
dc.date.none.fl_str_mv 2021
2021
2021
2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/178671
url https://hdl.handle.net/2445/178671
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1186/s12943-021-01370-2
Molecular Cancer, 2021, vol. 20
https://doi.org/10.1186/s12943-021-01370-2
dc.rights.none.fl_str_mv cc by (c) Bellon et al., 2021
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by (c) Bellon et al., 2021
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 15 p.
application/pdf
dc.publisher.none.fl_str_mv Springer Nature
publisher.none.fl_str_mv Springer Nature
dc.source.none.fl_str_mv Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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