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

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.

The benefit of a complete reference genome for cancer structural variant analysis

“…From the 49 somatic SVs detected in COLO829-lifted (45 TP and 4 FN), 35 SVs overlap with 26 known genes, of which 25 are related to cancer. Some examples are FHIT (near a fragile site), tumor suppressors ITIH5, MAGI2, PTEN, WWOX, and cell-proliferation control gene TMX3 (Bellon et al 2021; Cao et al 2020; Yehia et al 2023; Husanie et al 2022; Zhang et al 2019).…”

“…B) IGV screenshot of an SV that was labeled as FN according to the benchmark by Valle-Inclan et al Our analysis calls removed thee SVs due to lack of evidence in all samples (Supplementary Table 13)Overall, the approach of incorporating alignment to CHM13-T2T followed by liftover analysis eliminated all FP somatic SV calls for COLO829. Such a reduction in FP has important impacts suppressors ITIH5, MAGI2, PTEN, WWOX, and cell-proliferation control gene TMX3(Bellon et al 2021;Cao et al 2020;Yehia et al 2023;Husanie et al 2022;Zhang et al 2019).…”

Increased H19/miR-675 Expression in Adult T-Cell Leukemia Is Associated with a Unique Notch Signature Pathway

“…Though the exact number of HTLV-I infected individuals is likely under-estimated, it is believed that in ubiquitous, hot-spot regions, 1-2% of persons are infected, with some foci reaching 20-40% of the population over the age of 55 [3]. HTLV-I infection appears to initiate the pathway toward ATL development; however, it is unknown whether preexisting conditions or genetic defects exist before HTLV-I infection that make a host cell vulnerable to ATL development [4]. Once infected, the expression of HTLV-I proteins, specifically the viral Tax protein, instigates genome and genetic instability, allowing for T-cell transformation that culminates in the development of ATL [5].…”

“…ATL cell lines (ATL43T, ATL55T, LM-Y1, KK1, KOB, SO4, 1185, LAF) were supplemented with 50 U/mL IL-2 and 20% FBS. Primary ATL patient samples have been used in previous studies [4,9]. ATL patient samples were obtained after informed consent.…”

Effects of DNA methylation and its application in inflammatory bowel disease (Review)

“…It is noteworthy that the FHIT gene also functions as a TSG. It is frequently methylated in tumor growth, although its function as a TSG is lost due to epigenetic alterations ( 108 ). Hence, the hypermethylation of the gene in CD may lead to gene suppression, leading to a loss of function in its TSG ability to suppress tumors.…”