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Subclonal genetic heterogeneity and their diverse gene expression impose serious problems in understanding the behavior of cancers and contemplating therapeutic strategies. Here we develop and utilize a capture-based sequencing panel, which covers host hotspot genes and the full-length genome of human T-cell leukemia virus type-1 (HTLV-1), to investigate the clonal architecture of adult T-cell leukemia-lymphoma (ATL). For chronologically collected specimens from patients with ATL or pre-onset individuals, we integrate deep DNA sequencing and single-cell RNA sequencing to detect the somatic mutations and virus directly and characterize the transcriptional readouts in respective subclones. Characteristic genomic and transcriptomic patterns are associated with subclonal expansion and switches during the clinical timeline. Multistep mutations in the T-cell receptor (TCR), STAT3, and NOTCH pathways establish clone-specific transcriptomic abnormalities and further accelerate their proliferative potential to develop highly malignant clones, leading to disease onset and progression. Early detection and characterization of newly expanded subclones through the integrative analytical platform will be valuable for the development of an in-depth understanding of this disease. Characterising the clonal architecture of Adult T-cell leukemia-lymphoma (ATL) remains crucial. Here, the authors develop a capture-based sequencing panel and use deep DNA and single cell RNA sequencing and report distinct genomic and transcriptomic features associated with subclonal evolution.

Human T‐cell leukemia virus type 1 (HTLV‐1) broadly impacts host genes, affecting the infected cell population and inducing the development of a disease with a poor prognosis, adult T‐cell leukemia‐lymphoma (ATL). This study aimed to provide a comprehensive epigenomic characterization of the infected cell population and evaluated the transcriptome and chromatin structures of peripheral blood cells in HTLV‐1‐infected individuals using RNA sequencing (RNA‐seq) and assay for transposase‐accessible chromatin sequencing (ATAC‐seq). The infected cells showed significant changes in gene expression patterns from the polyclonal stage and before ATL onset while demonstrating similarities to tumor‐forming ATL cells. These similarities were a result of large‐scale open chromatin changes, supporting the independent early formation of epigenomic aberrations as an underlying mechanism for later clonal propagation. This study also demonstrated that HTLV‐1 Tax directly affects the host chromatin structure, thereby developing fundamental epigenomic characteristics. Several Tax target genes, including the RASGRP3–ERK pathway, were recognized, indicating an impact on signaling pathways. This genome‐wide variability in chromatin structural property is a novel feature of HTLV‐1 infection and may contribute to pathogenic mechanisms. In addition, it has crucial implications for better understanding the impact of HTLV‐1 on the host genome and identifying novel therapeutic targets. We analyzed and evaluated cells infected with human T‐cell leukemia virus type 1 at different stages of infection in terms of gene expression and chromatin structure using ATAC sequencing and RNA sequencing. Our results revealed that infected cells exhibited significant changes in gene expression patterns from the polyclonal stage and before adult T‐cell leukemia‐lymphoma (ATL) onset while demonstrating similarities to tumor‐forming ATL cells. Additionally, our study also showed that Tax directly affects the host chromatin structure, resulting in the development of fundamental epigenomic characteristics, and that infected cells possess a remarkably different epigenomic structure and exhibit aberrant expression than normal T cells.

The main mode of mother-to-child transmission of the human T-cell leukemia virus (HTLV)-1 is through breastfeeding. Although the most reliable nutritional regimen to prevent HTLV-1 transmission is exclusive formula feeding, a recent meta-analysis revealed that short-term breastfeeding within 90 days does not increase the risk of infection. The protocol of the Japanese Health, Labor, and Welfare Science Research Group primarily recommended exclusive formula feeding for mothers who are positive for HTLV-1. However, there has been no quantitative research on the difficulties experienced by HTLV-1-positive mothers in carrying out these nutritional regimens, including the psychological burden. Therefore, this review was performed to clarify the burdens and difficulties encountered by mothers who are positive for HTLV-1; to this end, we analyzed the data registrants on the HTLV-1 career registration website “Carri-net” website. The data strongly suggest that it is not sufficient to simply recommend exclusive formula feeding or short-term breastfeeding as a means of preventing mother-to-child transmission; it is important for health care providers to understand that these nutritional regimens represent a major burden for pregnant women who are positive for HTLV-1 and to provide close support to ensure these women’s health.

The perception of human T-cell leukemia virus type 1 (HTlV-1) infection as a “silent disease” has recently given way to concern that its presence may be having a variety of effects. HTLV-1 is known to cause adult T-cell leukemia (ATL), an aggressive cancer of peripheral CD4 T cells; however, it is also responsible for HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Most patients develop ATL as a result of HTLV-1 mother-to-child transmission. The primary route of mother-to-child transmission is through the mother’s milk. In the absence of effective drug therapy, total artificial nutrition such as exclusive formula feeding is a reliable means of preventing mother-to-child transmission after birth, except for a small percentage of prenatal infections. A recent study found that the rate of mother-to-child transmission with short-term breastfeeding (within 90 days) did not exceed that of total artificial nutrition. Because these preventive measures are in exchange for the benefits of breastfeeding, clinical applications of antiretroviral drugs and immunotherapy with vaccines and neutralizing antibodies are urgently needed.

Epigenomes enable the rectification of disordered cancer gene expression, thereby providing new targets for pharmacological interventions. The clinical utility of targeting histone H3 lysine trimethylation (H3K27me3) as an epigenetic hallmark has been demonstrated 1 – 7 . However, in actual therapeutic settings, the mechanism by which H3K27me3-targeting therapies exert their effects and the response of tumour cells remain unclear. Here we show the potency and mechanisms of action and resistance of the EZH1–EZH2 dual inhibitor valemetostat in clinical trials of patients with adult T cell leukaemia/lymphoma. Administration of valemetostat reduced tumour size and demonstrated durable clinical response in aggressive lymphomas with multiple genetic mutations. Integrative single-cell analyses showed that valemetostat abolishes the highly condensed chromatin structure formed by the plastic H3K27me3 and neutralizes multiple gene loci, including tumour suppressor genes. Nevertheless, subsequent long-term treatment encounters the emergence of resistant clones with reconstructed aggregate chromatin that closely resemble the pre-dose state. Acquired mutations at the PRC2–compound interface result in the propagation of clones with increased H3K27me3 expression. In patients free of PRC2 mutations, TET2 mutation or elevated DNMT3A expression causes similar chromatin recondensation through de novo DNA methylation in the H3K27me3-associated regions. We identified subpopulations with distinct metabolic and gene translation characteristics implicated in primary susceptibility until the acquisition of the heritable (epi)mutations. Targeting epigenetic drivers and chromatin homeostasis may provide opportunities for further sustained epigenetic cancer therapies. The mechanisms of action and resistance of valemetostat, an EZH1–EZH2 dual inhibitor, in patients with adult T cell leukaemia/lymphoma who initially responded but later showed disease progression are explored.

We previously indicated that Hodgkin lymphoma (HL) cells contain a small side population (SP) that differentiate into a large major population (MP) with giant Hodgkin and Reed‐Sternberg (H and RS)‐like cells. However, its molecular mechanisms are not fully understood. In this study, we found that intracellular reactive oxygen species (ROS) are low in the SP compared to the MP. Hydrogen peroxide induces large H‐ and RS‐like cells in HL cell lines, but induces cell death in unrelated lymphoid cell lines. Microarray analyses revealed the enrichment of upregulated genes under hypoxic conditions in the SP compared to the MP, and we verified that the SP cells are hypoxic. Hypoxia inducible factor (HIF)‐1α was preferentially expressed in the SP. CoCl2, a HIF‐1α stabilizer, blunted the effect of hydrogen peroxide. Heme oxygenase‐1 (HO‐1), a scavenger of ROS, was triggered by HIF‐1α. The effect of hydrogen peroxide was inhibited by HO‐1 induction, whereas it was promoted by HO‐1 knockdown. HO‐1 inhibition by zinc protoporphyrin promoted the differentiation and increased ROS. These results stress the unique roles of ROS in the differentiation of HL cells. Immature HL cells are inhibited from differentiation by a reduction of ROS through the induction of HO‐1 via HIF‐1α. The breakdown of this might cause the accumulation of intracellular ROS, resulting in the promotion of HL cell differentiation. Immature HL cells are inhibited from differentiation by a reduction of ROS through the induction of HO‐1 via HIF‐1α. The breakdown of this might cause the accumulation of intracellular ROS, resulting in the promotion of HL cell differentiation.

Adult T‐cell leukemia/lymphoma (ATL) develops via stepwise accumulation of gene mutations and chromosome aberrations. However, the molecular mechanisms underlying this tumorigenic process are poorly understood. We previously reported the presence of a biological link between the expression of CD30, which serves as a marker for ATL progression, and the actively proliferating fraction of human T‐cell leukemia virus type 1 (HTLV‐1)‐infected cells that display polylobulation. Here, we demonstrated that CD30 signaling induced chromosomal instability with clonal expansion through DNA double‐strand breaks (DSBs) via an increase of intracellular reactive oxygen species. CD30+ATL cells were composed of subclones with additional genomic aberrations compared with CD30−ATL cells in ATL patients. Furthermore, we found an accumulation of copy number loss of DSB repair‐related genes as the disease progressed. Taken together, CD30 expression on ATL cells appears to be correlated with genomic instability, suggesting that CD30 signaling is one of the oncogenic factors of ATL progression with clonal evolution. This study provides new insight into the biological roles of CD30 signaling and could improve our understanding of tumorigenic processes of HTLV‐1‐infected cells. CD30 signaling induced chromosomal instability through DSBs via an increase of intracellular reactive oxygen species in CD30‐expressing ATL cells. These results highlight that endogenous signaling by CD30 is an oncogenic signal that promotes ATL progression and that CD30 is a promising target for treating aggressive ATL and inhibiting disease progression in indolent ATL.

Adult T-cell leukemia/lymphoma develops decades after Human T-lymphotropic virus type 1 (HTLV-1) infection. Factors like proviral load (PVL), soluble interleukin-2 receptors (sIL-2R), and clonality are associated with its pathogenesis. However, a comprehensive assessment using multiple factors of ATL development and progression based on flow cytometry (HAS-Flow) has not been performed. We conducted a 10-year clinical follow-up of 160 asymptomatic people living with HTLV-1 using HAS-Flow, PVL, sIL-2R, and the HTLV-1 integration site identification. The cases were classified into three groups based on cell adhesion molecule 1 (CADM1)-expressing cells by HAS-Flow: Group 1 (≤ 10%, 115 cases), Group 2 (> 10% to ≤ 25%, 33 cases), and Group 3 (> 25%, 12 cases). In the follow-up, no cases in Group 1 developed ATL, while five cases in Group 2 and nine in Group 3 did. Among the developed ATL, one case in Group 2 and six in Group 3 progressed to aggressive ATL. Higher CADM1-expressing cells and sIL-2R levels were linked to earlier ATL development. The HTLV-1 integration site was identified in all aggressive ATL cases. Thus, evaluating CADM1-expressing cells by HAS-Flow, assessing sIL-2R, and identifying the HTLV-1 integration site can better predict ATL development and progression to aggressive ATL.

T cells infected with human T-cell leukemia virus type 1 (HTLV-1) acquire various abnormalities during a long latent period and transform into highly malignant adult T-cell leukemia-lymphoma (ATL) cells. This can be described as “clonal evolution”, in which a single clone evolves into ATL cells after overcoming various selective pressures in the body of the infected individuals. Many studies have shown that the genome and epigenome contain a variety of abnormalities, which are reflected in gene expression patterns and define the characteristics of the disease. The latest research findings suggest that epigenomic disorders are thought to begin forming early in infection and evolve into ATL through further changes and accentuation as they progress. Genomic abnormalities profoundly affect clonal dominance and tumor cell characteristics in later events. ATL harbors both genomic and epigenomic abnormalities, and an accurate understanding of these can be expected to provide therapeutic opportunities.