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

Molecular Cancer

Genoveffa Franchini¹  Veronica Galli¹  Izabela Bialuk¹  Xue-Tao Bai²  Toshiki Watanabe³  Marcia Bellon⁴  Christophe Nicot⁴  Achilea Bittencourt⁵  Lee Ratner⁶  Ambroise Marçais⁷  Olivier Hermine⁷  Masao Matsuoka⁸  Michael N. Petrus⁹  Thomas A. Waldmann⁹  Lourdes Farre^1,10  Antoine Gessain^1,11  Vahid Asnafi^1,12 

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

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

DOI  :  10.1186/s12943-021-01370-2

来源: Springer

【 摘 要 】

BackgroundHuman 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.MethodsHere, 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.ResultsWe 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.ConclusionsThese 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.

【 授权许可】

CC BY