Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of relapsed/refractory hematologic malignancies, achieving remarkable response rates in B-cell acute lymphoblastic leukemia and lymphomas. However, treatment responses and toxicities vary substantially among patients, necessitating the establishment of robust predictive biomarkers for optimal patient stratification and treatment personalization. This review systematically categorizes key factors affecting CAR-T therapy efficacy into tumor-intrinsic and T cell-intrinsic components. Tumor-intrinsic factors include tumor burden, antigen expression heterogeneity, and immunosuppressive components within the tumor microenvironment, such as regulatory T cells, myeloid-derived suppressor cells, tumor-associated macrophages, and inhibitory cytokines (e.g., TGF-β and IL-10). T cell-intrinsic factors encompass memory T cell subset composition, particularly central memory and stem cell memory populations, CAR expression density and transduction efficiency, polyfunctional cytokine production profiles, mitochondrial function and metabolic fitness, and expression of immune checkpoint molecules. Recent technological advances in single-cell RNA sequencing, comprehensive proteomics, and high-dimensional immunophenotyping combined with machine learning algorithms enable increasingly precise biomarker identification and predictive modeling. Integration of these multidimensional biomarkers into unified prediction models holds substantial promise for personalizing therapy, enhancing efficacy while minimizing adverse events, and ultimately achieving durable remission in patients receiving CAR-T therapy.

A 55-year-old man was referred to our hospital with weight loss, somnolence, and dysarthria. Laboratory tests revealed elevation of serum creatinine (2.17 mg/dl), serum corrected calcium (16.3 mg/dl), and parathyroid hormone-related protein (PTHrP, 3.7 pmol/l). 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) demonstrated splenomegaly and increased FDG uptake in the spleen and in bone marrow throughout the body. Bone marrow biopsy showed infiltration of large atypical lymphoid cells. The neoplastic cells were positive for CD20, BCL-6, MUM1, PTHrP, and PTH1 receptor on immunohistochemical staining, prompting a diagnosis of PTHrP-producing diffuse large B-cell lymphoma (DLBCL). After one cycle of R-CHOP chemotherapy, the PTHrP level became undetectable; after four cycles, a complete metabolic response was confirmed on PET/CT. The patient subsequently underwent autologous peripheral blood stem cell transplantation and achieved long-term complete remission. PTHrP-producing DLBCL is extremely rare, and further investigation is needed to better understand its disease characteristics and pathophysiology.

Allogeneic hematopoietic stem cell transplantation is the only curative treatment for myelofibrosis. However, the high risk of non-relapse mortality and the difficulty of finding an HLA-matched sibling donor are obstacles, given the advanced age at disease onset. Here, we report four cases of transplantation from an HLA-haploidentical donor using post-transplant cyclophosphamide (PTCy-haplo) in three recipients with primary (n=1) and secondary (n=2) myelofibrosis. The median age was 52 years, and one patient had received JAK2 inhibitor therapy prior to transplantation. The sources were bone marrow and peripheral blood stem cells (two cases each); myeloablative conditioning was used in two cases. Neutrophil engraftment was achieved in all cases (median 19 days); however, prolonged G-CSF administration (median 44 days) was required, and platelet engraftment was delayed (median 68 days). Two patients survived without relapse, with observation periods of 3.5 and 8 years, respectively. One patient relapsed 17 months after the first transplantation and died of pneumonia 49 days after second PTCy-haplo. These findings suggest that PTCy-haplo is a feasible option for patients with myelofibrosis; however, the risk of delayed hematopoietic recovery should be noted.

Mesenchymal stem cells (MSCs) have emerged as a leading cell source in regenerative medicine due to their multipotency and immunomodulatory capabilities. In recent years, extracellular vesicles (EVs) derived from MSCs have attracted increasing attention as a novel, cell-free therapeutic modality, exhibiting many of the biological effects similar to their parent cells. This review outlines the current status and future prospects of MSC-derived EVs, focusing on their therapeutic mechanisms, standardization efforts, and regulatory trends in Japan and overseas. We further discuss the challenges in the development of EV-based products, including scalable manufacturing, quality control strategies, viral safety, and impurity profiling. The application of Quality by Design (QbD) and single-particle analytics is also highlighted as a means to enhance product consistency and clinical reliability. MSC-EVs have the potential to revolutionize treatment paradigms for various refractory diseases, but their successful implementation will require harmonization of scientific, technical, and regulatory frameworks. This review provides a comprehensive overview of the translational pathway from basic research to clinical and commercial application of MSC-EV therapeutics.

Extracellular vesicles (EVs) are cell-derived membrane vsicles that contain biologically active molecules, such as proteins and nucleic acids, originating from EV-producing cells. Because EVs can deliver their contents to recipient cells, they exert biological effects via intercellular delivery. Accordingly, EVs derived from certain types of mammalian cells, particularly mesenchymal stem cells, can be used as therapeutic agents by utilizing their biological properties. Therefore, mammalian cell-derived EVs are considered the most promising EVs for therapeutic applications. However, several critical challenges must be addressed before EV-based therapies can be successfully implemented. These include elucidating the pharmacokinetics of EVs, and establishing robust methods for their large-scale production and validation. This review outlines the current progress in overcoming these challenges and discusses the remaining issues that need to be addressed to enable the practical application of EV-based therapies in clinical settings.

Human fetal ventral mesencephalic tissue transplantation provided early evidence supporting the efficacy of cell replacement therapy for Parkinson's disease; however, major challenges, including ethical concerns and graft-induced dyskinesia (GID), were raised. Recently, clinical trials using dopaminergic progenitor cells derived from induced pluripotent or human embryonic stem cells have demonstrated favorable safety profiles, graft survival, and the apparent absence of GID. Well-designed clinical trials are required to confirm the safety and establish its definitive clinical efficacy.

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.