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Bellon M, Bialuk I, Galli V, et al. Germinal epimutation of Fragile Histidine Triad (FHIT) gene is associated with progression to acute and chronic adult T-cell leukemia diseases. Mol Cancer. 2021;20(1):86doi: 10.1186/s12943-021-01370-2.
Bellon, M., Bialuk, I., Galli, V., Bai, X. T., Farre, L., Bittencourt, A., Marçais, A., Petrus, M. N., Ratner, L., Waldmann, T. A., Asnafi, V., Gessain, A., Matsuoka, M., Franchini, G., Hermine, O., Watanabe, T., & Nicot, C. (2021). Germinal epimutation of Fragile Histidine Triad (FHIT) gene is associated with progression to acute and chronic adult T-cell leukemia diseases. Molecular cancer, 20(1), 86. https://doi.org/10.1186/s12943-021-01370-2
Bellon, Marcia, et al. "Germinal epimutation of Fragile Histidine Triad (FHIT) gene is associated with progression to acute and chronic adult T-cell leukemia diseases." Molecular cancer vol. 20,1 (2021): 86. doi: https://doi.org/10.1186/s12943-021-01370-2
Bellon M, Bialuk I, Galli V, Bai XT, Farre L, Bittencourt A, Marçais A, Petrus MN, Ratner L, Waldmann TA, Asnafi V, Gessain A, Matsuoka M, Franchini G, Hermine O, Watanabe T, Nicot C. Germinal epimutation of Fragile Histidine Triad (FHIT) gene is associated with progression to acute and chronic adult T-cell leukemia diseases. Mol Cancer. 2021 Jun 06;20(1):86. doi: 10.1186/s12943-021-01370-2. PMID: 34092254; PMCID: PMC8183032.
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Mol Cancer. 2021 Jun 06;20(1):86. doi: 10.1186/s12943-021-01370-2.

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

Molecular cancer

Marcia Bellon, Izabela Bialuk, Veronica Galli, Xue-Tao Bai, Lourdes Farre, Achilea Bittencourt, Ambroise Marçais, Michael N Petrus, Lee Ratner, Thomas A Waldmann, Vahid Asnafi, Antoine Gessain, Masao Matsuoka, Genoveffa Franchini, Olivier Hermine, Toshiki Watanabe, Christophe Nicot

Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA.
  2. Animal Models and Retroviral Vaccines Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  3. Comprehensive Cancer Center, Department of Health Sciences, Ohio State University, Columbus, OH, USA.
  4. Program in Molecular Mechanisms and Experimental Therapy in Oncology, IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.
  5. Department of Pathology, Prof. Edgard Santos Teaching Hospital, Federal University of Bahia, Salvador, Bahia, Brazil.
  6. Institut Necker-Enfants Malades, Institut National de la Santé et de la Recherche Médicale U1151, Laboratoire Onco-Hématologie, Paris, France.
  7. Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  8. Division of Oncology, Department of Medicine, Washington University, St Louis, MO, USA.
  9. Université de Paris (Descartes), Institut Necker-Enfants Malades, Institut National de la Santé et de la Recherche Médicale (INSERM) U1151 Laboratoire Onco-Hematology, Paris, France.
  10. Unité d'épidémiologie et de Physiopathologie des virus Oncogene, Institut Pasteur, 75015, Paris, France.
  11. Centre National de la Recherche Scientifique (CNRS) UMR 3569, 75015, Paris, France.
  12. Laboratory of Virus Control, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto, Japan.
  13. Department of Hematology, Rheumatology, and Infectious Disease, Graduate School of Medical Sciences, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan.
  14. Department of Hematology/Oncology, IMSUT Hospital, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  15. Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, 66160, USA. [email protected].

PMID: 34092254 PMCID: PMC8183032 DOI: 10.1186/s12943-021-01370-2

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.

Keywords: ATL; ATLL; Cancer; Epigenetic; Epimutation; FHIT; HAM; HTLV-1; Leukemia; Lymphoma; Methylation; TSP; TSP/HAM; Tax

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