Adult T-cell leukemia-lymphoma (ATL) is a malignancy of peripheral CD4+ T cells induced by human T-cell leukemia virus type 1 (HTLV-1). HTLV-1 encodes two oncogenic viral factors, Tax and HTLV-1 bZIP factor (HBZ) in the sense and antisense strands of the provirus respectively. Both Tax and HBZ dysregulate the expression and activities of a large number of host genes and cellular signaling pathways via their multimodal functions. Tax is a potent transactivator of viral replication and various cancer-related genes in HTLV-1-infected cells; however, Tax expression is generally suppressed in ATL cells owing to its high immunogenicity. Previously, we reported that Tax is transiently expressed in a small subpopulation of ATL cells, leading to drastic changes in the host transcriptional profile. In contrast, HBZ is conserved and expressed in all ATL patients. The HBZ gene is thought to be essential in the pathogenesis of HTLV-1. It is unique in that its transcript not only encodes HBZ protein but also acts in a similar way to long non-coding RNAs. Among the functions of HBZ, activation of the TGF-β/Smad pathway is critical for proliferation of ATL cells. These multimodal actions of Tax and HBZ genes are thought to be critical for ATL leukemogenesis.

Acute myeloid leukemia (AML) is becoming more prevalent as the Japanese population ages, highlighting the growing importance of individualized treatment based on age, comorbidities, and genetic abnormalities. This review outlines the significant transformation in AML management after the introduction of azacitidine plus venetoclax, FLT3 inhibitors, and CPX-351. It also discusses HEM-SIGHT, a next-generation sequencing panel developed in Japan that became covered by Japanese national health insurance in 2025, enabling a molecularly stratified approach to diagnosis. Despite advances in treatment, several subtypes including TP53-mutated and MECOM-overexpressing AML remain highly refractory, even with allogeneic stem cell transplantation and targeted therapies. These high-risk entities pose ongoing therapeutic challenges. The current paradigm in AML treatment has shifted toward strategic personalization, encompassing molecular abnormality identification, measurable residual disease assessment, and treatment adaptation based on these findings. To achieve wider adoption of precision medicine in clinical practice, Japan must continue strengthening its diagnostic systems, streamlining genomic testing in routine practice, and integrating these strategies with novel therapeutic development.

Recent advances in molecular genetic research, driven by the development of genomic analysis technologies, have significantly improved treatment outcomes for leukemia. In recent years, mounting evidence indicates that germline genetic background influences drug sensitivity and the risk of adverse effects, underscoring the growing importance of personalized treatment strategies. In particular, the NUDT15 polymorphism, which determines sensitivity to 6-mercaptopurine, has garnered significant attention. Notably, a low-activity variant of this polymorphism, prevalent in Asian countries, has been shown to substantially increase the risk of bone marrow suppression and other adverse effects. Pre-treatment analysis of the NUDT15 polymorphism has demonstrated utility in dose adjustment, helping to mitigate the risk of treatment-related toxicities. Studies have also explored the relationship between genetic background and late complications of leukemia treatment. Optimization of therapeutic strategies based on pharmacogenetic insights holds promise for minimizing complications while maximizing treatment efficacy for each individual patient.

Adult T-cell leukemia/lymphoma (ATL) has a very poor prognosis with conventional multidrug chemotherapy. Lenalidomide, an oral anticancer drug classified as an immunomodulator, showed an overall response rate of 46% in a phase II clinical trial in relapsed ATL. The antibody therapy mogamulizumab showed an overall response rate of 50% in a phase II trial of relapsed C-C motif chemokine receptor 4-positive ATL. Brentuximab vedotin has yet to show clear evidence of efficacy due to the limited number of patients enrolled in phase II trials. Epigenetic therapy has also been investigated. The EZH1/2 inhibitor valemetostat showed a response rate of 48% in a phase II trial in relapsed/refractory aggressive ATL. The histone acetylation inhibitor tucidinostat also exhibited efficacy in ATL, with an objective response rate of 30.4%. This review focuses on the abovementioned molecular-targeted agents, which are all currently used in Japan.

In lung cancer, circulating tumor DNA(ctDNA)analysis has already been clinically implemented, for example, to detect resistance mutations to EGFR-TKIs. Recently, as in many other cancer types, postoperative detection of molecular residual disease (MRD) has been shown to correlate with poor prognosis. This article summarizes the latest findings on MRD research in lung cancer. A literature review as of May 2024 identified 41 studies on lung cancer MRD. Although no randomized trials have yet utilized MRD to guide treatment decisions in this field, retrospective studies consistently demonstrate its utility in predicting recurrence. In Japan, prospective studies such as JCOG2111A(MRDSEEKER trial, NCT06854939), which evaluates the kinetics and detection rate of MRD using a tumor-informed personalized assay, are currently underway. Notably, recent subset analyses of ctDNA/MRD assessments before and after treatment in randomized trials on perioperative chemoimmunotherapy and adjuvant therapy have garnered significant attention. However, the sensitivity of the assays used in these studies possibly remains suboptimal for lung cancer. Future prospective trials incorporating more sensitive, second-generation assays may be warranted.

Conventionally, hereditary tumor syndromes have been identified on the basis of clinical features, including characteristic tumor types and family history. Therefore, it is important for clinicians to consider hereditary tumor syndromes and collect detailed patient background information. However, recent advancements in genetic analyses have enabled the molecular diagnosis of these syndromes. This review addresses the recommendation of genetic counseling for affected patients and their families. In addition, the key points of the updated World Health Organization classification of central nervous system tumors are summarized.

Synovial sarcoma is a type of soft tissue sarcoma that predominantly occurs near the joints of the extremities in young adults. Its hallmark is a recurrent and pathogenic chromosomal translocation, t(X;18)(p11.2;q11.2), which results in the fusion of the SSX1 or SSX2 gene with SS18. The expressed SS18-SSX fusion protein induces abnormalities in the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex, a chromatin remodeling complex. In this paper, we refer specifically to the human SWI/SNF complex as mSWI/SNF. Since 2020, significant progress has been made in elucidating the molecular mechanisms underlying the initial event in synovial sarcomagenesis, particularly in structural biology, thereby opening new possibilities for structure-based drug design (SBDD). SS18-SSX1 replaces the wild-type SS18, an essential subunit of mSWI/SNF, and in turn ejects SMARCB1, another core subunit of the complex. This aberrant mSWI/SNF complex (ssSWI/SNF) is then relocated to nucleosomes containing H2A K119Ub. H2A is one of the core histone proteins, and its 119th lysine residue is ubiquitinated to form H2A K119Ub. Chromatin domains harboring nucleosomes with this modification typically exhibit suppressed gene expression patterns. Furthermore, this region is occupied by polycomb complexes, but ssSWI/SNF competes with them, leading to gene activation, which constitutes the initial event in synovial sarcomagenesis. Given that SSX1 is normally expressed primarily in the testes, it is plausible that its ectopic expression leads to aberrant function within the chromatin remodeling complex. Ultimately, the C-terminal region of SSX1 was found to bind to the acidic patch within the nucleosome, and its structural details have been elucidated through cryo-electron microscopy.

Claudins(CLDNs)are essential components of tight junctions, which are the most apical elements of apical junctional complexes. The family consists of more than 20 members in humans and shows distinct expression patterns in a tissue- and cell-type-specific manner. Recently, many studies have shown that CLDNs overexpressed in cancer cells positively regulate their malignant behavior. First, fusion genes between CLDNs and signaling molecules produce chimeric proteins that act as drivers. Second, cancer and non-cancer cells form heterocellular adhesions via CLDNs and they act as a metastatic niche. Third, CLDNs enhance cancer cell nutrition by conjugating with amino acid transporters on the cell membrane. Fourth, CLDN acts as an activation trigger for signalling cascades. In this review, we present these 4 representative examples of how CLDNs positively regulate cancer progression.

An elevated expression of claudins(CLDNs), tight junctional proteins, are reported in various solid tumors. However, the expression mechanisms and pathophysiological roles of CLDNs have not been well clarified. So far, we found that CLDN2 and CLDN14 are highly expressed in lung adenocarcinoma and colorectal cancer cells, respectively. These CLDNs augmented proliferation of cancer cells. Furthermore, these CLDNs enhanced chemoresistance of cancer spheroids mediated by the elevation of oxidative stress and activation of Nrf2 signal pathway. The restriction of glucose supply, shift of glucose metabolism from aerobic glycolysis towards oxidative phosphorylation, and elevation of mitochondria activity were suggested to be involved in the CLDN2-dependent activation of Nrf2 signal pathway. The CLDN expression inhibitors are expected to have functions of proliferation inhibition and anticancer drug resistance improvement effects. We have to search for the optimal CLDN subtype as therapeutic target because the expression pattern of CLDN subtypes is different in the type of cancer.

EVI1 is a zinc finger transcription factor encoded by the MECOM locus and is essential for the development and maintenance of hematopoietic stem cells. However, overexpression of EVI1 in various myeloid malignancies is associated with aggressive clinical behavior and poor outcome. The locus encodes multiple isoforms that are differentially acting and independently regulated. EVI1 interacts with a variety of transcription and epigenetic factors via different domains. It also regulates cell survival, differentiation, and proliferation through a variety of mechanisms, including transcriptional activation and repression, regulation of other transcription factors' activity, and chromatin remodeling. While the mechanism by which 3q26 translocation leads to high EVI1 expression through enhancer hijacking of genes active in myeloid development is now better understood, regulation of EVI1 expression in the absence of chromosomal translocations and in normal hematopoiesis remains unclear. Recent studies have provided insight into the regulatory mechanisms of EVI1 expression and action, which may lead to development of targeted therapies in the near future.

Flow cytometry (FCM) remains an essential test in the diagnosis of leukemia despite advances in genomic testing. However, the role of FCM results as a risk factor is already extremely limited. International diagnostic criteria for leukemia already prioritize diagnosis based on genetic abnormalities, with FCM diagnosis only serving as an aid to morphological diagnosis for subtypes without genetic abnormalities. However, rapid lineage diagnosis of leukemia by FCM remains important for selecting initial treatment. FCM is also an important tool for evaluating response to molecular targeted therapy, which requires repeated measurements and rapid results. Furthermore, FCM enables prediction of specific genetic abnormalities by immunophenotypic patterns, which could make it useful for verifying the clinical impact of genetic abnormalities detected by multi-gene panel testing.

Multiple myeloma (MM) is a hematologic malignancy characterized by clonal proliferation of plasma cells. Recent advances in next-generation sequencing technologies have facilitated in-depth genetic exploration of MM, unveiling a more comprehensive genomic landscape that extends beyond classical chromosomal alterations, such as IGH translocations and hyperdiploidy. These studies have elucidated recurrent mutations across various functional pathways including those involving MAPK, NF-κB, cell cycle regulation, and epigenetic modulation. With respect to clinical utility, studies have shown that the number of genetic alterations and biallelic events in TP53 are associated with worse prognosis, and CRBN mutations with resistance to immunomodulatory drugs. We recently analyzed the full landscape of genetic alterations in relapsed and refractory MM using circulating tumor DNA (ctDNA), revealing TP53 mutations as the most frequent driver mutation. Notably, more than half of TP53 mutations were present in only ctDNA, suggesting a subclonal origin. Mutations in six genes, including KRAS and TP53, were associated with poor progression-free survival. In addition, the number of ctDNA mutations was identified as a prognostic factor independent of IGH translocations and clinical factors. Here we summarize recent progress in genetic analysis of MM, focusing on clinical relevance.

Adult T-cell leukemia/lymphoma (ATLL) is an aggressive peripheral T-cell malignancy caused by human T-cell leukemia virus type-1 (HTLV-1) infection. Genetic alterations are thought to contribute to the pathogenesis of ATLL alongside HTLV-1 products such as Tax and HBZ. Several large-scale genetic analyses have delineated the entire landscape of somatic alterations in ATLL, which is characterized by frequent alterations in T-cell receptor/NF-κB pathways and immune-related molecules. Notably, up to one-fourth of ATLL patients harbor structural variations disrupting the 3'-UTR of the PD-L1 gene, which facilitate escape of tumor cells from anti-tumor immunity. Among these alterations, PRKCB and IRF4 mutations, PD-L1 amplification, and CDKN2A deletion are associated with poor prognosis in ATLL. More recently, several single-cell transcriptome and immune repertoire analyses have revealed phenotypic features of premalignant cells and tumor heterogeneity as well as virus- and tumor-related changes of the non-malignant hematopoietic pool in ATLL. Here we summarize the current understanding of the molecular pathogenesis of ATLL, focusing on recent progress made by genetic, epigenetic, and single-cell analyses. These findings not only provide a deeper understanding of the molecular pathobiology of ATLL, but also have significant implications for diagnostic and therapeutic strategies.

Myelodysplastic syndrome (MDS) is a refractory cancer that arises from hematopoietic stem cells and predominantly affects elderly adults. In addition to driver gene mutations, which are also found in clonal hematopoiesis in healthy elderly people, systemic inflammation caused by infection or collagen disease has long been known as an extracellular factor in the pathogenesis of MDS. Wild-type HSCs have an "innate immune memory" that functions in response to infection and inflammatory stress, and my colleagues and I used an infection stress model to demonstrate that the innate immune response by the TLR-TRIF-PLK-ELF1 pathway is similarly critical in impairment of hematopoiesis and dysregulation of chromatin in MDS stem cells. This revealed that not only are MDS stem cells expanded by the TRAF6-NF-kB pathway, the innate immune response is also involved in generating MDS stem cells. In this review, I will present research findings related to "innate immune memory," one of the pathogenic mechanisms of blood cancer, and discuss future directions for basic pathological research and potential therapeutic development.

Biological molecular studies of meningiomas have also developed with the development of molecular biological methods. In 2013, Clark et al. reported that driver genetic mutations other than NF2, including TRAF7, KLF4, AKT1, and SMO, were associated with meningioma development. In 2017, Sahm et al. proposed a classification of meningiomas based on global methylation status, which was more accurate in predicting prognosis than conventional WHO grading. In 2022, based on this classification, various groups reported an integrated classification that comprehensively included some biological molecular abnormalities, such as DNA mutations, copy number alterations, and RNA sequences. This field is expected to elucidate the mechanism of meningioma development and further research is expected to lead to the development of effective molecularly targeted therapeutics and biomarkers of radiosensitivity in the future. In this article, we summarize the current status and prospects of these biological molecular studies.

Meningiomas, renowned for their histological diversity, are one of the most prevalent brain tumors. Some meningiomas show unusual histomorphology, especially in intraoperative rapid diagnosis. Therefore, clinical and radiological information is crucial for pathological diagnosis. Before the 2021 World Health Organization Classification of Tumors of the Central Nervous System(5th edition), pathological diagnosis relied solely on histopathological features. However, this classification introduced new diagnostic criteria for anaplastic meningiomas, which now include TERT promoter mutations and the homozygous deletion of CDKN2A/B, indicating the necessity of genetic analysis. Some rhabdoid and papillary meningiomas have BAP1 alterations, which tend to demonstrate an aggressive clinical course and may represent a phenotype of BAP1-related tumor predisposition syndrome. Heterozygous deletion of CDKN2A/B and loss of H3 p.K28me3(K27me3)are also associated with poor prognosis. Although some immunohistochemical markers like MTAP may serve as surrogates for the homozygous deletion of CKKN2A/B, genetic analysis is required to confirm TERT promoter mutations. Therefore, in routine clinical practice, neurosurgeons and pathologists prioritize appropriate formalin fixation to facilitate genetic analysis using pathological specimens.

Chronic activation of the nuclear receptor, peroxisome proliferator-activated receptor alpha (PPARA), causes hepatocellular proliferation and increases the incidence of hepatocellular carcinoma in rodents. However, the molecular mechanisms underlying hepatocyte proliferation by activated PPARA remain ambiguous. This review focuses on the genes repressed by PPARA and describes the mechanism by which it promotes hepatocyte proliferation in mice. PPARA undergoes autoinduction, leading to its overexpression by an agonist. PPARA subsequently activates the E2F transcription factor 8 (E2f8), which then activates the ubiquitin-like protein containing the PHD and RING finger domains 1 (Uhrf1). UHRF1, in complex with histone deacetylase 1 and DNA methyltransferase 1, stimulates DNA methylation and recruitment of histone H3 containing trimethylated lysine 9 to the promoters of specific target genes, including E-cadherin/cadherin 1 (Cdh1), resulting in their downregulation. Decreased expression of CDH1 stimulates Wnt signaling, upregulation of oncogenes, including Myc and the cell cycle control genes, cyclin D1 and Jun, and enhances hepatocyte hyperproliferation. Therefore, the PPARA-E2F8-UHRF1-CDH1-Wnt signaling axis is involved in the epigenetic regulation of hepatocyte proliferation. This review provides insights into the mechanisms underlying hepatocarcinogenesis induced by non-genotoxic substances.

This review focuses on cancer, a serious health issue in modern society, and explores the advancements and applications of single-cell RNA sequencing(scRNA-seq)as an advanced technique for understanding its pathobiology. Cancer often arises due to genetic mutations or epigenetic changes, which manifest through fluctuations in gene expression. Therefore, transcriptome information(transcriptomics)plays an indispensable role in cancer research. In this field, there has been a shift from hybridization to next-generation sequencing, and the emergence of scRNA-seq technology enables the analysis of dynamic gene expression properties at the single-cell level. Consequently, significant advancements have been made in cancer research, including understanding complex intercellular variations and interactions, as well as revealing the roles of the tumor microenvironment and immune cells, and the contribution of non-coding RNAs. This review focuses on the progress and applications of scRNA-seq technology, providing an overview of new insights and prospects for cancer research and therapy.

der(1;7)(q10;p10) is a derivative chromosome generated by an unbalanced translocation between chromosomes 1 and 7 during DNA replication. It was first described in 1980, over 40 years ago, in a case report of three patients with myelofibrosis and myeloid metaplasia. This unbalanced translocation has been identified as a characteristic entity within myeloid neoplasms. Recent clinical and genetic studies comparing der(1;7)(q10;p10)(+) against -7/del(7q) have revealed that patients with der(1;7)(q10;p10)(+) MDS have a better prognosis and a unique mutational profile. This review discusses the clinical and genetic features of der(1;7)(q10;p10)(+) myeloid neoplasms.

Anthracycline- and cytarabine-based intensive combination chemotherapies are considered the backbone therapy for patients with acute myeloid leukemia (AML). Although chemotherapy leads to long-term remission and cures many patients with AML, it can induce DNA damage/stress due to acute/chronic toxicities, acquired resistance, relapse, and therapy-related malignancies. Introduction of molecularly targeted agents with less systemic toxicities has considerably improved the scope of treatment, particularly in elderly and frail patients. However, outcomes of TP53-mutated myelodysplastic syndrome (MDS) and AML, a distinct group of myeloid disorders, have not improved irrespective of the treatment used (median overall survival, 5-10 months). In this review, we discuss the biological and clinical significance of TP53 mutations in malignancies, while particularly focusing on MDS/AML, and emerging therapies for TP53-mutated MDS/AML. Rationally designed novel treatment strategies are expected to improve the clinical outcomes of TP53-mutated MDS/AML.