Germinal epimutation of Fragile Histidine Triad (FHIT) gene is associated with progression to acute and chronic adult T-cell leukemia diseases
| Autor: | Olivier Hermine, Vahid Asnafi, Izabela Bialuk, Marcia Bellon, Lee Ratner, Ambroise Marçais, Michael N. Petrus, Thomas A. Waldmann, Genoveffa Franchini, Toshiki Watanabe, Antoine Gessain, Masao Matsuoka, Christophe Nicot, Achiléa L. Bittencourt, Lourdes Farre, Veronica Galli, Xue Tao Bai |
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| Přispěvatelé: | University of Kansas Medical Center [Kansas City, KS, USA], National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Ohio State University [Columbus] (OSU), Hospitalet de Llobregat, Universidade Federal da Bahia (UFBA), Institut Necker Enfants-Malades (INEM - UM 111 (UMR 8253 / U1151)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Washington University in Saint Louis (WUSTL), Epidémiologie et Physiopathologie des Virus Oncogènes (EPVO (UMR_3569 / U-Pasteur_3)), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Kyoto University, Kumamoto University, The University of Tokyo (UTokyo), This work was supported by grant R01CA201309 to Christophe Nicot. |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
MESH: Neoplasm Proteins Cancer Research MESH: Paraparesis Tropical Spastic Lymphoma [SDV]Life Sciences [q-bio] viruses T-cell leukemia Bisulfite sequencing Tax MESH: Acid Anhydride Hydrolases Epigenesis Genetic TSP/HAM 0302 clinical medicine MESH: DNA Methylation FHIT immune system diseases hemic and lymphatic diseases Tropical spastic paraparesis Leukemia-Lymphoma Adult T-Cell MESH: Epigenesis Genetic MESH: Leukemia-Lymphoma Adult T-Cell Càncer RC254-282 Cancer Leukemia Neoplasms. Tumors. Oncology. Including cancer and carcinogens Epigenetic virus diseases Leucèmia TSP Paraparesis Tropical Spastic Acid Anhydride Hydrolases Neoplasm Proteins Oncology 030220 oncology & carcinogenesis Disease Progression Molecular Medicine MESH: Disease Progression Epigenetics Tumor suppressor gene Biology ATLL Methylation 03 medical and health sciences MESH: HTLV-I Infections medicine Humans Epimutation neoplasms Retrospective Studies MESH: Humans Research MESH: Retrospective Studies DNA Methylation medicine.disease Epigenètica HTLV-I Infections HAM 030104 developmental biology ATL HTLV-1 Cancer research |
| Zdroj: | Dipòsit Digital de la UB Universidad de Barcelona Molecular Cancer Molecular Cancer, 2021, 20 (1), pp.86. ⟨10.1186/s12943-021-01370-2⟩ Molecular Cancer, Vol 20, Iss 1, Pp 1-15 (2021) |
| ISSN: | 1476-4598 |
| DOI: | 10.1186/s12943-021-01370-2⟩ |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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