While acute myeloid leukemia (AML) treatment has significantly advanced in recent years, many promising novel agents remain unapproved in Japan. This review focuses on menin inhibitors and covers IDH inhibitors, oral azacitidine, antibody-drug conjugates, bispecific antibodies, radioisotope therapies, and CAR-T cell therapies for AML. Menin inhibitors, which are particularly effective against AML with KMT2A rearrangements or NPM1 mutations, have shown promising results in clinical trials. These novel agents may expand treatment options and improve outcomes for AML patients.

Acute myeloid leukemia (AML) is common in elderly adults and is a genetically heterogeneous disease. Many factors such as adverse chromosomal and/or genetic abnormalities contribute to disease risk, along with defining features related to antecedent hematologic disorders and a history of exposure to radiation or cytotoxic agents in the case of secondary AML. The "7+3" regimen combining cytarabine and anthracycline, along with its reduced-dose variant, was once the only first-line treatment option for AML in Japan. However, treatment options have expanded in recent years to include azacitidine with or without venetoclax, as well as CPX-351 and quizartinib combination chemotherapy. Nevertheless, there are still many high-risk conditions with a low chance of cure even with these new drugs or allogeneic transplantation, and many other issues remain to be addressed. This article outlines the current best treatment options and future prospects for high-risk disease types.

Acute myeloid leukemia (AML) is associated with various genetic abnormalities in its development and progression, which also affect treatment response and prognosis. The advent of gene panel testing is expected to clarify the involvement of these genetic mutations, which will provide useful information for treatment decision-making and prediction of prognosis in clinical practice. Some therapies have already been developed for actionable mutations: quizartinib for FLT3-ITD mutations is available for newly diagnosed AML, and ivosidenib for IDH1 mutations is awaiting approval. Knowledge of baseline genetic characteristics also allows for diagnosis according to the ICC 2022 and 5th edition of the WHO Classification, as well as risk stratification by the ELN2022 risk classification for patients receiving intensive chemotherapy and ELN2024 risk classification for patients receiving reduced-intensity chemotherapy. CPX-351, a liposomal formulation of cytarabine and daunorubicin, has also shown efficacy in patients with MDS-related gene mutations. Decisions on allogeneic transplantation and accessibility of investigational drugs are also expected. Detailed diagnosis and prognosis prediction based on the profile of genetic abnormalities should enable precision medicine.

The Ser/Thr-specific kinase, polo-like kinase 1 (Plk1), is a crucial eukaryotic cell cycle regulatory protein. Overexpression of this kinase is observed in many cancer cells and where it can be related to their aggressiveness. Dysfunction of Plk1 in cancer cells causes mitotic arrest and subsequent apoptosis. Accordingly, Plk1 is considered as a target for the development of anti-cancer agents. Plk1 has two domains, a catalytic kinase domain (KD) and a polo-box domain (PBD). PBD intramolecularly interacts with its KD and regulates Plk1 activity and localization. Therefore, in addition to the KD, the PBD is considered to be a potential drug target. We have been developing peptidic low-nanomolar-affinity PBD-binding inhibitors. However, these peptides do not show significant cytotoxicity, due to their low cell membrane permeability. To obtain cell-active Plk1 inhibitors, I applied a bivalent approach designed to simultaneously engage both KD and PBD regions of Plk1 for enhancing the potency, selectivity and lipophilicity. Here, I developed bivalent Plk1 inhibitors, in which the PBD-binding peptides are conjugated with the known KD-binding inhibitors BI2536 or wortmannin using PEG linkers. These bivalent inhibitors exhibit up to 100-fold enhanced Plk1 affinity relative to the best monovalent PBD-binding ligands, higher selectivity for tested kinases compared to BI2536, and significant cytotoxicity against HeLa cells.

Venetoclax, a BCL-2 inhibitor, has transformed the treatment of elderly patients with acute myeloid leukemia (AML), but resistance remains a major clinical challenge. Approximately 30% of patients exhibit primary resistance, and many relapse despite achieving remission. Resistance mechanisms are multifaceted. AML stem cells rely on oxidative phosphorylation (OXPHOS) for survival, and venetoclax disrupts this energy metabolism by inducing mitochondrial dysfunction. However, resistant cells activate compensatory pathways such as fatty acid oxidation, amino acid metabolism, and the MEK-ERK signaling axis. Expression of anti-apoptotic proteins such as MCL-1 and BCL-XL also increases, circumventing BCL-2 inhibition. Furthermore, rare BCL2 mutations can directly impair drug binding. Sensitivity or resistance to venetoclax correlates strongly with specific molecular abnormalities. TP53 mutations predict poor response and survival, while RAS and FLT3 mutations confer moderate resistance. In contrast, IDH1/2 and NPM1 mutations are associated with high treatment sensitivity. Moving forward, personalized treatment strategies based on genetic profiles, along with combination therapies targeting metabolism or anti-apoptotic escape pathways, hold promise in overcoming resistance and improving outcomes in AML.

Treatment for acute myeloid leukemia (AML) in older adults has traditionally focused on adjusting treatment intensity and expanding the indications for the 3+7 regimen and allogeneic stem cell transplantation. However, recent advances, particularly the introduction of venetoclax plus azacitidine, have significantly improved outcomes. New agents such as quizartinib, CPX-351, venetoclax plus low-dose cytarabine, gemtuzumab ozogamicin, and ivosidenib have also emerged. Low-intensity treatment options, especially regimens incorporating molecularly targeted agents, offer potential survival benefits for older patients. Consequently, selecting and combining these therapies with conventional treatments has become a significant challenge in clinical practice. In treatment decision-making, it is essential to utilize a comprehensive geriatric assessment, which evaluates not only disease factors but also physical and cognitive function, nutritional status, and social background. It is particularly important to identify the molecular prognostic risk signature based on genetic mutation data and apply stratification models to carefully assess disease factors. This comprehensive approach ensures a tailored treatment strategy. This article provides an overview of AML in older adults and current treatment options in Japan, as well as discusses future drug developments and necessary approaches to make informed treatment decisions.

Acute lymphoblastic leukemia (ALL) is a hematologic neoplastic disease characterized by monoclonal proliferation of lymphoid progenitor cells that have ceased to differentiate, primarily in the bone marrow. Although outcomes of adult ALL remain poorer than those of pediatric ALL, they have dramatically improved in the past decade with better understanding of prognostic factors and the advent of novel therapies. In particular, BCR-ABL1 tyrosine kinase inhibitors and targeted agents against cell surface antigens (CD19, CD20, and CD22) have revolutionized the treatment of ALL. Clinical adoption of genomic screening and sensitive MRD assays should also inform appropriate treatment selection based on recurrence risk. This article outlines the current classification approach for ALL stratification and discusses future prospects for ALL treatment strategies.

RNA processing, including splicing, polyadenylation, and capping, plays a central role in post-transcriptional gene regulation. Recent genomic studies have revealed frequent mutations in RNA processing factors, particularly splicing factors such as SF3B1, SRSF2, U2AF1, and ZRSR2, in hematologic malignancies. These mutations result in aberrant splicing, contributing to tumorigenesis and disease progression. In this review, we summarize the molecular consequences of these mutations and their pathophysiological impact. We discuss shared downstream mechanisms such as R-loop accumulation, impaired transcriptional elongation, and the generation of immunogenic neoantigens derived from abnormal splicing. We also review recent advances in therapeutic strategies targeting splicing dysregulation, including small molecule splicing modulators and antisense oligonucleotides. These approaches offer the potential for selective targeting of cancer cells with aberrant RNA processing. Novel strategies to exploit splicing abnormalities for cancer treatment are emerging as understanding of RNA processing biology progresses and precision RNA-based therapeutics are developed.

Treatment strategies for chronic myeloid leukemia (CML) have changed significantly with the development of new tyrosine kinase inhibitors (TKIs). Due to its extreme rarity, pediatric CML has historically been managed based on evidence in adult patients. However, as the unique biological and clinical characteristics of pediatric CML have become increasingly apparent, the need for pediatric-specific treatment guidelines is now widely recognized. This review outlines the treatment of pediatric CML as of 2025, with a focus on clinical trial results from Japan and the latest consensus guidelines issued by the International Pediatric CML Working Group.

The advent of novel anti-multiple myeloma (MM) agents has led to dramatic improvement in patient survival. Nevertheless, the majority of patients with MM have bone lesions, and destructive bone lesions significantly reduce quality of life. Progressive destructive bone lesions develop when osteoblast differentiation from bone marrow stromal cells is inhibited and osteoclasts are activated in the bone marrow microenvironment in patients with MM. Recent research has also shed light on the functions and roles of osteocytes, which account for the majority of bone cells. Since MM cells mainly invade the red marrow, bone lesions are often found in the skull, spine, and ilium, which contain red marrow. Imaging is essential for the diagnosis of MM bone lesions, and whole-body low-dose CT, whole-body MRI, and FDG-PET/CT have demonstrated utility. Furthermore, recent advances in anti-MM drugs have improved the prognosis of MM significantly, highlighting the importance of treating and managing MM bone lesions. This review will explain the molecular pathology and management of MM bone lesions.

Follicular lymphoma (FL) has a wide spectrum of clinical manifestations, ranging from cases that require little or no treatment to cases that are refractory to any treatment. In recent years, advances in DNA and RNA profiling, as well as analysis of the tumor microenvironment, have progressively increased understanding of the underlying molecular pathogenesis of FL. Early progression of disease following immunochemotherapy includes histologic transformation to a more aggressive phenotype, which is associated with poor survival outcomes. Recent advances beyond conventional immunochemotherapy, including small molecular compounds, bispecific antibodies, and CAR-T cell therapy, have expanded therapeutic options and improved prognosis for FL patients. Research suggests that factors associated with treatment efficacy and prognosis may not be consistent across therapeutic agents. A deeper understanding of the molecular biology of FL should pave the way for optimized, individualized treatment sequences.

Clonal hematopoiesis is a condition in which hematopoietic cells undergo clonal expansion, often accompanied by the acquisition of driver gene mutations. This is now known to occur inevitably in elderly adults as somatic mutations accumulate in hematopoietic stem cells with aging. Various driver genes associated with clonal hematopoiesis-such as epigenetic regulators and signaling molecules-have been identified, many of which are shared with hematological malignancies. It takes approximately 30 years from the acquisition of the initial driver mutation in clonal hematopoiesis to the onset of hematological cancer, and genetic background also contributes to the initiation and progression of clonal hematopoiesis. Furthermore, clonal hematopoiesis is not only involved in the development of hematological malignancies, but also plays a role in the onset and progression of cardiovascular diseases and cancers in other organs. In the future, the development of therapies targeting clones with driver mutations is also anticipated.

Asciminib is a first-in-class allosteric inhibitor that specifically targets the myristoyl pocket of BCR::ABL1 and has shown efficacy in patients with chronic myeloid leukemia (CML) who are resistant or intolerant to prior tyrosine kinase inhibitors (TKIs). Despite its unique mechanism of action, several resistance mechanisms to asciminib have been identified. BCR::ABL1 kinase domain mutations, including A337V, C464W, and compound mutations involving T315I, can interfere with asciminib binding or allosteric regulation. Additionally, BCR::ABL1 transcript variants lacking the SH3 domain, such as e13a3 and e14a3, exhibit primary resistance by disrupting the autoinhibited conformation required for asciminib activity. Non-BCR::ABL1 mechanisms that also contribute to resistance include overexpression of efflux transporters such as ABCG2 and P-glycoprotein, which reduce intracellular drug accumulation. Moreover, novel insertion mutations like p.I293_K294insSLLRD have been shown to impair the allosteric inhibition of ABL1. Combination therapies with ponatinib or other agents, as well as newer TKIs like olverembatinib, have demonstrated potential in overcoming resistance in preclinical and clinical models. Understanding these diverse resistance mechanisms is critical for optimizing asciminib-based treatment strategies and guiding the development of effective combination therapies for patients with resistant CML.

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.