Chronic myeloid leukemia (CML) is driven by the BCR::ABL1 fusion gene, and the introduction of tyrosine kinase inhibitors (TKIs) has dramatically improved long-term survival. In Japan, five agents-imatinib (Glivec®), dasatinib (Sprycel®), nilotinib (Tasigna®), bosutinib (Bosulif®), and STAMP inhibitor asciminib (Scemblix®)-are currently approved for first-line therapy. Each has distinct efficacy and toxicity profiles, requiring individualized treatment decisions based on age, comorbidities, cardiovascular risk, fertility, adherence, and financial factors. Recent advances have shifted treatment goals from disease control to treatment-free remission (TFR), with imatinib, dasatinib, and nilotinib supported by robust clinical trial data. Emerging strategies, such as low-dose regimens and step-up dosing of TKI, highlight the importance of balancing efficacy with tolerability and quality of life. Looking forward, immunologic determinants of TFR and novel therapeutic approaches, including targeting CML stem cells with agents such as asciminib or demethylating drugs, may offer prospects for cure. This review summarizes the current evidence and practical considerations in selecting first-line therapy for chronic-phase CML, with a focus on optimizing long-term outcomes and advancing toward individualized and potentially curative strategies.

Steroid hormone receptors (SRs) play pivotal roles in the fundamental biological functions related to reproduction, development, and homeostasis. They are also closely associated with various pathophysiologies, including hormone-dependent cancers, metabolic syndromes, and neuropsychiatric disorders. SRs are ligand-dependent transcription factors belonging to the nuclear receptor superfamily. This superfamily also includes orphan nuclear receptors, such as estrogen-related receptors (ERRs) comprising three subtypes of α, β, and γ. Despite their high homology with estrogen receptors (ERs), ERRs cannot bind any endogenous steroid hormones and can activate gene transcription in a ligand-independent manner. Recently, ERRs have attracted considerable attention for their involvement in stem cell pluripotency, senescence, and other poorly understood biological processes. Although subcellular and subnuclear dynamics are crucial for SR function, how ERRs behave in living cells to activate or repress their target genes remains incompletely understood. We have investigated the behaviors of ERRs using fluorescent protein labeling, focusing on whether ERRs exhibit dynamic changes similar to SRs and whether these changes relate to their functional activity. In this review, we summarize findings from studies of molecular behavior, highlighting the coregulation of estrogen signaling by ERs and ERRs, the subnuclear movement of ERRs related to transcriptional repression, and the promotion of lactate metabolism by a novel lactate-responsive protein, LRPGC1, through interaction with ERRγ. We hope these insights contribute to elucidating fundamental biomedical processes and the pathological mechanisms linked to aberrant nuclear receptor signaling pathways.

Brain microvascular endothelial cells (BMECs) are the central cellular components of the blood-brain barrier (BBB) that protect the central nervous system. The characteristic functions of the BBB, such as its strong barrier properties and selective regulation of molecular transport into the brain, are largely mediated by BMECs. Human induced pluripotent stem cell-derived BMECs (iBMECs) have garnered attention because of their robust tight junction integrity and transporter activity, distinguishing them from cells used in conventional BBB models. In recent years, iBMECs have shown great promise for drug discovery and disease modeling, particularly through integration with organ-on-a-chip technologies and the use of disease-specific iPS cells to construct disease-mimicking BBB models. This article provides an overview of the current state and future prospects of iBMECs, highlighting advances in differentiation techniques, cellular characteristics, and their emerging applications.

Skeletal muscle possesses remarkable plasticity and regenerative capacity, supported by satellite cells (skeletal muscle stem cells) that can respond to both physical and chemical stimuli by activation and differentiation. Recently, the ability of stem cells to adapt to environmental changes has been conceptualized as "resilience," emerging as a key topic in stem cell biology. This review focuses on how satellite cells sense mechanical perturbations during muscle regeneration and convert them into biological responses, highlighting the roles of the mechanosensitive ion channels PIEZO1 and TRPM7. PIEZO1 regulates proliferative responses in accordance with substrate stiffness, whereas TRPM7 promotes the retraction of quiescent projections and cellular activation via Mg2+ influx, also functioning upstream of the mTOR pathway to modulate the cell cycle and differentiation. These findings suggest that the mechanotransductive responses of satellite cells are multilayered and mechanosensitive ion channel-specific.

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.

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.

In immune aplastic anemia, somatic loss of specific HLA class I alleles enables hematopoietic stem cells to evade T-cell-mediated destruction. In Japanese patients, HLA-B*40:02, HLA-A*02:06, HLA-A*02:01, HLA-A*31:01, and HLA-B*54:01 are frequently lost and are also overrepresented, suggesting their involvement in the pathogenic antigen presentation. Detection of HLA-deficient blood cells is useful for distinguishing immune aplastic anemia from non-immune bone marrow failure syndromes. Furthermore, the specific lost HLA class I alleles correlate with clinical outcomes following immunosuppressive therapy and allogeneic hematopoietic stem cell transplantation. Hematologic recovery after successful antithymocyte globulin-based immunosuppressive therapy is driven by the reexpansion of HLA-intact hematopoietic stem cells. However, recent evidence indicates that spontaneous remission occurs through the selective proliferation of HLA-deficient clones in the absence of antithymocyte globulin. This review outlines the historical context, detection strategies, and clinical significance of HLA loss in aplastic anemia.

HLA class II molecules play a central role in antigen presentation that underlies the pathogenesis of graft versus host disease (GVHD) following allogeneic hematopoietic stem cell transplantation. This review introduces the concept of "neo-self" antigens observed in autoimmune diseases and applies it to chronic GVHD, where DBY/HLA class II complexes trigger pathological B cell activation, complement deposition, and tissue fibrosis. In acute GVHD, non-hematopoietic epithelial cells such as intestinal epithelial cells also contribute to disease by presenting antigens via HLA class II. In acute myeloid leukemia relapse, downregulation of HLA class II on leukemic cells allows immune evasion, but this suppression can be reversed by IFN-γ or flotetuzumab, a CD123×CD3 bispecific antibody, restoring immunogenicity and potentially enhancing the graft versus leukemia (GVL) effect. Collectively, HLA class II molecules function not only in conventional antigen presentation to CD4+ T cells but also in neo-self antigen recognition, immune evasion, and tissue-specific disease expression. A deeper understanding of HLA class II biology may pave the way toward therapeutic strategies that separate GVHD from the GVL effect.

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.

Recent technological advances have enabled the identification of numerous genetic abnormalities and have facilitated the accurate classification of childhood myelodysplastic neoplasia (MDS). Childhood MDS is characterized by clonal defects in hematopoietic stem and progenitor cells, leading to ineffective hematopoiesis and an increased risk of leukemic transformation-similar to adult MDS. However, childhood MDS is biologically distinct from its adult counterpart, differing in the spectrum of driver genes involved in transformation and showing a higher incidence of germline mutations commonly seen in inherited bone marrow failure syndromes (IBMFS) and hereditary myeloid malignancies. Childhood MDS often presents with hypocellular bone marrow, overlapping significantly with conditions such as aplastic anemia and IBMFS, which can make clinical differentiation challenging. Comprehensive genomic profiling using multigene panel testing offers the potential for more precise diagnosis and tailored treatment of childhood MDS and related myeloid malignancies.

Myeloproliferative neoplasms (MPNs) are a group of disorders characterized by the activation of the JAK/STAT signaling pathway at the level of hematopoietic stem cells. In one subtype, myelofibrosis (MF), JAK inhibitors have become the standard therapy for high-risk patients who are not eligible for hematopoietic stem cell transplantation. While current JAK inhibitors can alleviate disease-related symptoms, they have not yet been shown to modify the disease course or achieve a cure. In contrast, a watchful waiting approach is generally adopted for asymptomatic low-risk MF. Recently, advances in our understanding of the molecular pathogenesis of MPNs have led to the development of novel therapeutic strategies that could alter disease progression in addition to managing symptoms and complications. This article reviews the latest basic research on the pathogenesis and progression of MPNs, and provides an overview of current and emerging treatment strategies, with a particular focus on MF.

Antiretroviral therapy (ART) is a well-established treatment for HIV infection that suppresses viral replication by inhibiting viral enzymatic activity, thereby preventing progression to immunodeficiency. However, discontinuation of ART typically leads to rapid viral rebound within weeks, due to the reactivation of latent HIV from long-lived reservoirs such as resting CD4+ T cells. Eradication of these latent reservoirs is essential to achieve a cure for HIV. In 2009, the first case of HIV cure was reported: an individual with HIV and acute leukemia received an allogeneic hematopoietic stem cell transplant (HSCT) from a donor homozygous for the CCR5Δ32 mutation, which results in the absence of the HIV coreceptor CCR5. After ART interruption, the patient maintained undetectable plasma viremia without viral rebound. Since then, a total of nine cases with similar post-transplant virological remission have been documented globally. This review summarizes the clinical characteristics of reported cases of HIV cure, outlines the shock-and-kill strategy targeting latent HIV reservoirs, and discusses the current progress in the development of therapies to cure HIV using latency-reversing agents (LRAs).

In recent years, the "translational gap" has become problematic in drug development, wherein promising results from animal experiments and in vitro tests fail to demonstrate the expected efficacy and safety in clinical trials. This translational gap has also impacted on the development of therapeutic agents for brain diseases, including Alzheimer's disease (AD). While microglia, which are immune cells in the brain, have gained attention as therapeutic targets of AD, the inter-species difference in microglia between humans and experimental model animals may cause this gap. To reveal the pathogenic mechanisms of AD and develop a therapeutic strategy, experimental models that appropriately reproduce pathological conditions using human-derived materials are required. Pluripotent stem cells can differentiate into various cells such as neurons and microglia. Therefore, it is expected that the creation of neural organoids from human pluripotent stem cells will enable the construction of a human-based analysis system that can reproduce three-dimensional brain structures and intercellular interactions, thereby overcoming the translational gap. Furthermore, combining patient-derived induced pluripotent stem cells and gene editing technology with neural organoid technology is leading to cutting-edge research. In this review, we introduce global research trends aimed at developing neural organoids containing microglia derived from human pluripotent stem cells and applying them to elucidate the pathogenesis and to develop therapeutic drugs for AD.

The cancer-immunity cycle has been proposed, and immunotherapeutic approaches, such as vaccines using self-antigens and adjuvant, have been employed for a long time, but their therapeutic effects have been limited. However, recent studies have demonstrated that immune checkpoint inhibitors(ICIs)are able to achieve high therapeutic efficacy, in a variety of cancer types. Today, advances in multi-omics technologies, including single-cell RNA sequencing(scRNA-seq), spatial transcriptomics, and multicolor immunostaining technologies, have made it possible to analyze immune cell dynamics at the single-cell level in a greater detail. While CD8+ T cells play a central role in the antitumor immune response, recent findings have revealed the existence of various subsets within the CD8+ T cell population. During the research on T cell exhaustion, the in vivo dynamics of T progenitor exhausted cells(Tpex cells)/stem cell memory T cells(TSCM)have also been elucidated. Tpex/TSCM cells are present in tumor-draining lymph nodes and within tumors and have reported to be an important target for ICIs. Furthermore, interactions between CD4+ T cells, dendritic cells(DCs), B cells, and CD8+ T cells within the tumor microenvironment are crucial for the induction of cytotoxic CD8+ effector T cells. In human tumor tissues, cancer cells exhibit heterogeneous characteristics and the tumor microenvironment varies depending on cancer type, subtypes, and individual patients. To enhance the anti-tumor effects of CD8+ T cells in immunotherapy, it is essential to achieve a more precise understanding of the in vivo dynamics of CD8+ T cells in each patient and to develop strategies for their effective intervention. This knowledge will then be applied to the development of vaccine therapies, combination immunotherapies, and cellular immunotherapy.

Danicopan (brand name: Voydeya® tablets) is a new oral small molecule complement factor D inhibitor that was approved in Japan in January 2024 for paroxysmal nocturnal hemoglobinuria (PNH). PNH is a rare, chronic hematologic disorder caused by acquired mutations of hematopoietic stem cells in the PIGA gene. These mutations cause deficiencies in complement regulatory proteins CD55 and CD59 that may lead to uncontrolled terminal complement activation, intravascular hemolysis, thrombosis, and premature mortality. Complement C5 inhibitors (C5i; eculizumab and ravulizumab) are the current standard of care of PNH treatment, and control intravascular hemolysis (IVH) by inhibiting terminal complement pathway activation. However, extravascular hemolysis (EVH) with persistent symptoms, such as anemia, occurs in some C5i-treated patients with PNH. EVH is caused by the accumulation of proximal complement C3 fragment on the membrane of surviving PNH-type red blood cells. These cells subsequently undergo phagocytosis in the spleen or liver. Danicopan was developed to control EVH by targeting complement factor D involved in alternative pathway activation. Preclinical studies showed that danicopan selectively inhibits alternative complement pathway activation by reversibly binding to factor D and inhibiting its serine protease activity. A global phase III study (ALPHA study: ALXN2040-PNH-301 [NCT04469465]) investigated danicopan as add-on therapy to ravulizumab or eculizumab in patients with PNH and clinically significant EVH. Danicopan achieved statistically significant, clinically meaningful increases in hemoglobin levels, reduced transfusion, and reduced fatigue, while maintaining control of IVH. No new safety concerns were observed. Danicopan makes it possible to control EVH while controlling IVH with C5i.

Cord blood, which is rich in hematopoietic stem/progenitor cells, is now an important cell source for allogeneic hematopoietic cell transplantation (HCT). Although cord blood transplantation (CBT) was initially only performed in pediatric patients due to the limited number of cells, it now accounts for around 30% of allogeneic HCT for adults in Japan. It has overcome the shortage of donors caused by the declining birthrate and aging population. Although the greatest disadvantage of CBT is the high incidence of Engraftment failure, it has been shown that even in HLA-incompatible recipients, graft-versus-host disease (GVHD) is less frequent and less severe in CBT, whereas the graft-versus-leukemia (GVL) effect is stronger. CBT in Japan differs from that in other countries in that a single-unit is used in adult patients, and CBT is actively performed in elderly patients and patients with advanced hematopoietic disease. Based on the Japanese analysis, the usefulness of intensified conditioning regimen, the survival-improving effect on mild acute or chronic GVHD, and the strong GVL effect are all characteristic of CBT, which is an important source of cells for allogeneic HCT.

Non-clinical pharmacological safety studies are conducted using cells and animals to ensure the safety of pharmaceuticals in humans. Following these studies, drug candidates are administered to humans during clinical trials. Safety must be sufficiently confirmed in non-clinical studies to ensure that test participants suffer no adverse health effects. However, due to species differences, low ability to extrapolate from in vitro to in vivo evaluation methods, and other problems, health hazards may unfortunately still occur. Therefore, sophisticated in vitro evaluation systems using human cells are actively being pursued. The main challenge remains the lack of a reliable methodology for extrapolating in vitro results to in vivo settings. We have attempted to extract parameters that can be predictably translated from in vitro [contractile evaluation in three-dimensional (3D) heart tissue] to in vivo (guinea pig echocardiography) conditions, using cardiac contractile dysfunction induced by anticancer drugs as an example. In this review, we introduce the in vitro methods developed to date to evaluate this cardiac contractile dysfunction, analyze the factors enabling highly accurate prediction of torsades de pointes in humans based on past proarrhythmic risk prediction methods using human induced pluripotent stem cell-derived cardiomyocytes, and apply them to evaluate cardiac contractile dysfunction caused by anticancer drugs using three-dimensional heart tissue. We also introduce the proposed strategy for this evaluation method in this section.

To increase success rates of clinical studies, preclinical evaluation systems have been expected to improve human predictability. In addition, future preclinical studies need to become more sophisticated and efficient on the back ground of the adoption of FDA Modernization Act 2.0 and the 3R principle promotion of animal tests. In this review, we will discuss about the efficiency of in vivo imaging in preclinical studies taking 'an attempt to establishment of in vitro in vivo extraporation (IVIVE) model for seizure risk assessment using microphysiological system (MPS) and magnetic resonance imaging (MRI)', and 'an attempt to predict drug delivery to the alveoli' as examples. In the seizure risk assessment of new drugs so far, primary cultures of rodent neurons and in vivo behavioral observation have been mainly used, however, since the human induced pluripotent stem cell (iPSC) technology was reported, the need for IVIVE model is more and more increasing to improve human predictability. As an MPS, we here introduce microelectrode array (MEA) system recording of primary culture of rodent neurons, while as in vivo experiments, we here introduce the measurement of cerebrospinal fluid (CSF) concentrations and MRI imaging of forebrains of the rats i.p. injected with seizurogenic compounds. In case of inhalation drugs, it has been difficult to confirm whether or not the drugs surely reach alveoli. We visualized two-dimensional spatial localization of inhaled ciclesonide (CIC) in rat lungs after administration of a single dose of a CIC aerosol using by desorption electrospray ionization-time of flight mass spectrometry imaging (DESI-MSI).

Based on the perspectives of the environment, food, and health, this review reflects on previous research examining stem cells for the early detection of chemical hazards and the development of preventive health tools. The risks posed by endocrine-disrupting chemicals in the environment are investigated, including studies on 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), phthalate esters, and bisphenol A. Building on the findings of these studies, this review identifies emerging challenges in the field of endocrine-disrupting chemical research. Moreover, this paper explores innovative testing methods aimed at accurately evaluating the impact of chemicals on human health. The key topics covered include the implementation of developmental neurotoxicity testing methods, the species-specific effects of methylmercury, nanomaterials and the application of human pluripotent cells to assess the effects of low-dose radiation. Additionally, this review highlights transformative approaches in chemical health impact assessment that integrate cell science and artificial intelligence, and addresses challenges related to the application of multi-omics technologies in environmental health and toxicology.

Chronic obstructive pulmonary disease (COPD) is characterized by chronic bronchitis and emphysema, and current drug treatments is limited to symptomatic therapy. Thus, there is an urgent need for development of new treatments to repair alveolar destruction. To regenerate the destroyed alveoli, we focused on the differentiation of alveolar epithelial progenitor cells into type I or type II alveolar epithelial cells that constitute the alveoli. Our concept of alveolar regeneration therapy is based on developing a drug delivery system (DDS) and dry powder inhalation that can efficiently deliver new alveolar regeneration drugs, which were discovered using human alveolar epithelial progenitor cells, to stem cells present on the surface of the alveoli of COPD patients, thereby inducing alveolar regeneration. This review article summarizes our data on the discovery of the synthetic retinoid Am80 as a candidate drug for alveolar regeneration, the construction of a DDS that utilizes a biological mechanism that enhances its effect on alveolar regeneration, and the formulation design of a dry powder inhalation.