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Germinal epimutation of Fragile Histidine Triad (FHIT) gene is associated with progression to acute and chronic adult T-cell leukemia diseases
Molecular Cancer ( IF 37.3 ) Pub Date : 2021-06-06 , DOI: 10.1186/s12943-021-01370-2
Marcia Bellon 1 , Izabela Bialuk 2 , Veronica Galli 2 , Xue-Tao Bai 3 , Lourdes Farre 4 , Achilea Bittencourt 5 , Ambroise Marçais 6 , Michael N Petrus 7 , Lee Ratner 8 , Thomas A Waldmann 7 , Vahid Asnafi 9 , Antoine Gessain 10, 11 , Masao Matsuoka 12, 13 , Genoveffa Franchini 2 , Olivier Hermine 6 , Toshiki Watanabe 14 , Christophe Nicot 1
Affiliation  

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. 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. 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. 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.

中文翻译:

脆性组氨酸三联体 (FHIT) 基因的生发表突变与急性和慢性成人 T 细胞白血病疾病的进展有关

人类 T 细胞白血病病毒 1 型 (HTLV-I) 在病因学上与成人 T 细胞白血病/淋巴瘤 (ATL) 和称为 HTLV-I 相关性脊髓病或热带痉挛性截瘫 (HAM/TSP) 的炎性神经退行性疾病有关。影响 ATL 或 HAM/TSP 疾病发展的确切遗传或表观遗传事件和/或环境因素在很大程度上是未知的。肿瘤抑制基因,脆性组氨酸三联体二腺苷三磷酸酶 (FHIT),经常通过表观遗传修饰和/或缺失在癌症中丢失。FHIT 是一种肿瘤抑制因子,通过调节细胞 DNA 修复来充当基因组管理员。事实上,FHIT 损失会导致复制压力和双 DNA 链断裂的积累。因此,FHIT 表达的丧失在细胞转化中起关键作用。这里,我们研究了 400 多个来自 HTLV-I 感染个体的 ATL、TSP/HAM 或无症状携带者 (AC) 的 FHIT 丢失和表达样本。我们通过甲基化特异性 PCR 和亚硫酸氢盐测序检查了 FHIT 的表观遗传状态;并将这些结果与患者样本中的 FHIT 表达相关联。我们发现 FHIT 的表观遗传改变在慢性和急性 ATL 中特别发现,但在无症状 HTLV-I 携带者和 TSP/HAM 患者样本中不存在。此外,ATL 患者的 FHIT 甲基化程度在病毒感染和病毒未感染的细胞中在数量上相当。我们还发现,进展为阴燃 ATL 的纵向 HTLV-I 携带者和 ATL 患者的后代具有 FHIT 甲基化。这些结果表明,FHIT 的生发表观遗传突变代表了易患 ATL 疾病的预先存在的标记。这些发现具有重要的临床意义,因为急性 ATL 患者很少治愈。我们的研究提出了一种替代当前“观望方法”的策略,即早期筛查 HTLV-I 感染个体的 FHIT 生发表观突变和早期治疗可能会提供显着的临床益处。
更新日期:2021-06-07
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