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.

Myelodysplastic syndrome (MDS) is an abnormality of hematopoietic stem cells with limited effective drug therapy. Owing to the diversity of disease subtypes, treatment options must be decided on a case-by-case basis based on predictive prognostic scoring systems. The recently published revised WHO and ICC classifications incorporate genetic abnormalities into the diagnosis, and IPSS-M, which incorporates genetic mutations into the IPSS-R, allows for more individualized prognostic prediction. The treatment of low-risk MDS focuses on managing infection and bone marrow failure while preserving the quality of life: pharmacotherapy such as erythropoiesis-stimulating agents, lenalidomide, azacitidine, luspatercept, and allogeneic hematopoietic stem cell transplantation. The treatment choice depends on the profile at diagnosis and the results of predictive prognostic studies. Although there is little clear evidence regarding the timing of treatment initiation and goals of treatment, the NCCN guidelines suggest a hemoglobin level of 10-12 g/dl. Otsuka's HemeSight® hematological malignancy gene panel test, which will be introduced in Japan this year, is expected to contribute to the development of personalized treatments based on genetic information.

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.

A 54-year-old woman presented with a chief concern of right back pain that had persisted for 3 weeks. Laboratory tests revealed pancytopenia, liver dysfunction, and coagulation abnormalities. She had hepatomegaly and splenomegaly but no lymphadenopathy. No abnormal cells were detected in the bone marrow or on a liver biopsy. Epstein-Barr virus (EBV) DNA levels in the peripheral blood were high at 6.44 log IU/ml, and clonality of EBV-infected cells was confirmed by Southern blot hybridization with a probe targeting the EBV terminal repeat. EBV-infected NK cells were detected using the magnetic bead method. This led to a diagnosis of EBV-associated lymphoproliferative disease (EBV-LPD). As pancytopenia and coagulation abnormalities induced by the development of hemophagocytic syndrome continued to worsen after steroid therapy, we performed intensive chemotherapy followed by umbilical cord blood transplantation. After transplantation, EBV-DNA levels in the peripheral blood were undetectable, with complete donor chimerism. In the present case, the rapid disease progression with an extremely high EBV-DNA level indicated a poor prognosis. Intensive chemotherapy followed by upfront allogeneic hematopoietic cell transplantation may be necessary in patients with rapidly progressing EBV-LPD.

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.

Hematopoietic stem cells have the ability to self-renew and differentiate into multilineage cells. Therefore, hematopoietic stem cell gene therapy, which involves introducing therapeutic genes into these cells, could be an effective treatment for hereditary diseases currently targeted by hematopoietic cell transplantation. In fact, gene therapies using lentiviral vectors have already received manufacturing and sales approvals for several hereditary diseases. However, there are issues with this approach, such as tumorigenesis associated with the insertion of the vector genome and insufficient response to gain-of-function diseases caused by proteins derived from mutant genes. For this reason, the development of gene therapy using genome editing technology has become an active area of research in recent years. Nevertheless, because these technologies may cause permanent changes to the human genome, it is essential to proceed carefully with clinical development, based on social consensus.

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.

Multiple myeloma (MM) is a hematologic malignancy that primarily affects older adults. The advent of novel agents has improved treatment outcomes, even in elderly patients who are ineligible for autologous stem cell transplantation. In this population, both tumor-related factors (e.g., high-risk cytogenetic abnormalities) and host-related factors (e.g., frailty) are critical for predicting treatment outcomes and adverse events. Standard first-line therapies, including daratumumab (D)-based regimens (D-melphalan, bortezomib, and prednisolone, and D-lenalidomide and dexamethasone), have demonstrated significant survival benefits in phase III trials. Moreover, quadruplet therapy incorporating isatuximab has shown superiority over bortezomib, lenalidomide, and dexamethasone therapy in a recent phase III trial including relatively fit individuals. Emerging immunotherapies, including bispecific antibodies and chimeric antigen receptor-T cells targeting B-cell maturation antigen, have shown efficacy in relapsed/refractory MM. These agents are now being investigated as frontline treatments for transplant-ineligible patients and may become future standards of care. Furthermore, personalized treatment approaches that integrate clinical and biological factors-including depth of response, frailty status, and genetic alterations-are currently under development. Such approaches may facilitate the development of individualized therapies for this vulnerable population.

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.

Myelodysplastic syndromes (MDS) are clonal hematopoietic neoplasms caused by genetic abnormalities in hematopoietic stem cells and exhibit a heterogeneous clinical course. In the 2022 WHO classification (5th edition), the term was revised to "myelodysplastic neoplasms," reflecting their neoplastic nature, and both disease classification and prognostic stratification now incorporate genetic mutations. Diagnostic evaluation includes bone marrow examination with biopsy, iron staining, cytogenetic analysis, and comprehensive gene panel testing. Treatment strategies are determined based on risk stratification by the Revised International Prognostic Scoring System (IPSS-R) and the molecular IPSS (IPSS-M). In lower-risk MDS, supportive care remains the mainstay, with erythropoiesis-stimulating agents (ESAs), luspatercept, and lenalidomide as therapeutic options. In higher-risk cases, allogeneic hematopoietic stem cell transplantation remains the only curative therapy for eligible patients, while azacitidine is used for transplant-ineligible patients. As genomic profiling becomes more integrated into clinical practice, treatment selection based on specific genetic alterations is advancing, and further development of personalized therapy is anticipated.

Induced pluripotent stem cells (iPSCs) have been used in research for the development of treatments for various intractable diseases due to their unlimited proliferative and multipotent potential. We are aiming to develop novel therapies for intractable muscular diseases using iPS cells by two approaches i.e. cell therapy and drug screening. In this presentation, I focus on the cell therapy research. We have developed a differentiation induction method that mimics the developmental stages and have succeeded in inducing skeletal muscle stem cells that are applicable to cell transplantation therapy. We have found that cell transplantation into Duchenne muscular dystrophy (DMD) model mice is effective in regenerating more than 10% of dystrophin-positive fibers. In addition, some of the cells have been engrafted as satellite cells in vivo, and it is expected that the therapeutic effect will continue for a long period of time. As for the efficacy to the motor function, we have recently revealed that the regeneration of dystrophin positive myofibers in DMD model mice mainly ameliorates muscle fatigue tolerance rather than maximal contraction force in vivo. We have also developed a differentiation method to induce mesenchymal stromal cells (MSCs) from iPSCs. Transplantation of iPSC-derived MSCs (iMSCs) into Ullrich congenital muscular dystrophy (UCMD) model mice enabled the restoration of collagen type VI which resulted in enhancement of muscle regeneration. Interestingly, somatic MSCs such as bone marrow-derived MSC or adipose-derived MSC do not have therapeutic effect even they can also restore collagen type VI by the transplantation. We have recently found one of the candidates which is responsible for the muscle regeneration and is specifically expressed in the iMSCs.

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.

Nuclear medicine treatment is a treatment in which RI is administered to patients, and hematopoietic tumors were treated with 90Y-conjugated anti-CD20 antibodies for low-grade B-cell lymphoma from 2008 to 2021. Targeted α-particle therapy has attracted attention because they have a remarkable therapeutic effect and is effective in cases refractory to β-particle therapy. In Japan, astatine-211(211At)-labeled drugs are being developed due to the restriction of the production and supply of actinium-225(225Ac). Because hematopoietic tumors are sensitive to radiation and suitable for nuclear medicine therapy, the authors have been developing therapy with α radionuclides that target CD82, which is highly expressed in hematopoietic tumor stem cells. Overseas, the development of nuclear medicine treatment is progressing, and new drugs are being applied clinically one after another. In Japan, corporate clinical trials have been conducted and approved earlier than before. As a result, there will be a shortage of radiotherapy rooms that provide treatment and specialized medical personnel engaged in the treatment. In this article, we look at the future of conventional nuclear medicine therapies for hematopoietic tumors, the development of targeted α-particle therapy, and the problems as mentioned above.