Takuya Yamamoto

Donor polymorphisms in killer-cell immunoglobulin-like receptor (KIR) and HLA shape natural killer (NK) cell activity, which may influence relapse risk after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, association studies have been limited by insufficient allele-level KIR genotyping. Using high-resolution, long-read genotyping of 15 KIR genes, we performed an unbiased discovery analysis in 219 patients with T-cell leukemia/lymphoma (ATL) who underwent allo-HSCT to identify relapse-associated donor KIR/HLA polymorphisms. We comprehensively tested associations between donor KIR/HLA amino acid–level combinations and relapse risk, accounting for linkage disequilibrium across KIR haplotypes, and validated the findings in independent cohorts. In ATL, KIR3DL1∗005 or KIR3DS1∗013 with glutamic acid at position 62 in the HLA-B α2 domain (HLA-B-D2-62E) and KIR3DL1∗001/∗007/∗015/∗020 with HLA-B-D2-62V (valine) were high-risk (H) combinations. Meanwhile, KIR3DL1∗015 with isoleucine at position 80 in the HLA-B α1 domain (HLA-B-D1-80I) and KIR3DL1∗001/∗005/∗007/∗020 with HLA-B-D1-80T (threonine) were low-risk (L) combinations. Compared with L-/H+ donors (n = 119), L+/H-, L-/H-, and L+/H+ donors (n = 80) showed reduced relapse (adjusted hazard ratio [HR], 0.36; 95% confidence interval [CI], 0.19-0.65; P = 7.5 × 10-4) and improved overall survival (adjusted HR, 0.67; 95% CI, 0.45-0.98; P = .038). Those donors were associated with reduced relapse in other T-cell malignancies (n = 145; adjusted HR, 0.37; 95% CI, 0.16-0.89; P = .026) but not in acute myeloid leukemia (n = 965; P = .77), suggesting disease specificity. Low-risk combinations increased CD107a degranulation of KIR3DL1+ NK cells against HLA class I–deficient targets, consistent with enhanced NK cell education. These findings support KIR/HLA-based donor selection and underscore the role of antitumor NK cell immunity.

Osteosarcomas preferentially arise in the metaphysis of juvenile long bones, near the growth plate, unlike most cancers, whose incidence increases with age. Here, we show that p21, a negative regulator of the cell cycle, is induced in proliferating juvenile metaphyseal osteoblasts in response to DNA replication-associated damage. Single-cell RNA sequencing defines a differentiation hierarchy from multipotent progenitors to mature osteoblasts and identifies immature osteoblasts enriched for proliferation and replication stress responses. p21-positive metaphyseal osteoblasts associate with growth plate Indian hedgehog expression and decline after growth plate maturation or Hedgehog inhibition. c-Myc induction selectively promotes juvenile osteoblast proliferation despite p53 activation, but this proliferative response remains Hedgehog-dependent and ceases after growth plate maturation. By contrast, p53 inactivation enables sustained Hedgehog-independent proliferation of c-Myc -induced osteoblasts and lung metastasis. These findings reveal juvenile metaphyseal tissue homeostasis as a potential basis for the age of onset, anatomical specificity, and mutational profile of human osteosarcomas.

Cancer genome analysis relies on standard human reference genomes, but detecting somatic alterations in highly repetitive or individual-specific regions remains challenging. We developed the Personalized Reference genome-based Cancer Genome Analysis Pipeline (PRCGAP, https://github.com/yos-sk/PRCGAP), to our knowledge, the first comprehensive pipeline integrating haplotype-resolved analyses of somatic point mutations, structural variants, copy number, and DNA methylation on personalized diploid reference genomes, with each variant phased and annotated by genomic features. We applied PRCGAP to eight tumor-normal cell line pairs and three newly collected pediatric B-cell acute lymphoblastic leukemia (B-ALL) clinical samples. PRCGAP recovered most standard reference-based variants (86.7–96.4% across variant types), validated by orthogonal short-read sequencing, while additionally detecting variants that standard references missed (23.4% of SNVs and 32.6% of SVs). Notably, PRCGAP uncovered variants in centromeric and telomeric regions, and somatic single-nucleotide variants were enriched in centromere dip regions, the putative kinetochore formation sites. Using PRCGAP outputs, we identified L1 retrotransposition source sites absent from standard references and showed that a B-ALL IGH:: DUX4 fusion arose from a DUX4 pseudogene within an internal D4Z4 repeat unit, rather than the canonical full-length DUX4 gene. Within a single haplotype-resolved framework, PRCGAP opens regions of the cancer genome that are inaccessible to standard references.

Pancreatic cancers, whose incidence increases with age, are often refractory to treatment. Here, we identified a core mechanism shared by physiological homeostasis, senescent cell accumulation during aging, and pancreatic cancers. Pancreatic acinar cells, when stressed, secrete CXCL13, which protects stressed cells while transiently activating paracrine Hippo/YAP signaling to induce proliferation and PD-L1–mediated immune protection to maintain organ homeostasis. In the aged pancreas, CXCL13/YAP/PD-L1 signaling permits senescent cells to survive, driving feedforward chronic inflammation and steatosis. Because of prolonged CXCL13/YAP/PD-L1 activation in pancreatic cancers, neighboring noncancerous cells, activated for proliferation and immune-protected, eventually transform and accelerate tumor progression. CXCL13 blockade removed senescent cells and ameliorated steatosis in the aged pancreas while suppressing tumor growth in pancreatic cancer models, highlighting the CXCL13/YAP/PD-L1 axis as a potential therapeutic target. Together, our findings demonstrate the stress-induced CXCL13/YAP/PD-L1 axis as a central regulator of cell-state transitions in the pancreas, providing a unifying principle by which organ homeostasis, aging, and tumorigenesis are governed.

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive scarring of lung tissue with an urgent need for effective treatments. Studies have shown that the alveolar transitional cell state (ATCS) emerges in fibrotic regions of the IPF lung. However, whether ATCS is the cause or consequence of fibrosis is controversial, and no therapeutic agents targeting the alveolar epithelial differentiation are used to treat IPF. In this study, we performed a drug screening with an in vitro pulmonary fibrosis model using fibroblast-dependent alveolar organoids derived from human induced pluripotent stem cells (iPSCs) and identified p300/CBP inhibitors as candidate therapeutic agents. Multi-omics technology revealed that ATCS induced from human iPSCs-derived alveolar organoids had a compatible profile with that reported in IPF and p300/CBP inhibitors suppressed the emergence of ATCS. Overall, these results elucidate the biological mechanisms of pulmonary fibrosis and provide a potential therapeutic target.

Somatic Sertoli cells in the seminiferous tubule provide structural and paracrine support for spermatogenesis. Proper regulation of Sertoli cell cytoskeleton dynamics is essential for this function; however, the regulatory mechanisms remain unclear. Here, we found that polypyrimidine tract-binding protein 1 (PTBP1) maintained cytoskeletal integrity in Sertoli cells via mTORC2 signaling. Sertoli cell–specific Ptbp1 deletion in mice resulted in germ cell loss, blood–testis barrier disruption, and male infertility. Transcriptomic analysis of purified Sertoli cells revealed the dysregulation of cytoskeletal and adhesion-related genes. RNA immunoprecipitation sequencing demonstrated that PTBP1 bound to Rictor mRNA. PTBP1 loss reduced RICTOR protein expression and downstream PKCα activation, impairing the F-actin cytoskeleton. Cytoskeletal defects caused by PTBP1 deficiency were restored by constitutively active PKCα, confirming the functional relevance of the mTORC2–PKCα axis. These findings highlighted PTBP1’s role as a post-transcriptional regulator of male fertility through the maintenance of Sertoli cell architecture and spermatogenesis.

The pituitary gland plays a central role in maintaining physiological homeostasis by secreting multiple hormones that regulate diverse body functions. Dysregulation of pituitary hormones can arise from various conditions, such as pituitary tumors and autoimmune diseases, leading to a broad spectrum of symptoms. During embryonic organogenesis, the pituitary gland originates from the oral ectoderm in close contact with the adjacent hypothalamus. This tissue interaction is essential for proper development. Although the molecular mechanisms underlying pituitary development and related disorders have been extensively studied using animal models, such as rodents and zebrafish, species-specific differences limit the translatability of these findings to humans. Moreover, the scarcity of established human pituitary cell lines has hindered the investigation of human-specific mechanisms. Recent biotechnological advances have addressed these limitations by enabling the long-term culture of human pituitary tumor tissues and in vitro generation of pituitary hormone-producing cells from human pluripotent stem cells. These emerging platforms provide powerful tools for deepening our understanding of pituitary biology and diseases. In this review, we summarize current in vitro experimental models derived from pituitary tissues and pluripotent stem cells and discussed their applications in the study of pituitary development, physiology, and related disorders.

Thymic epithelial cells (TEC) are crucial in supporting T cell development, but their high heterogeneity and difficulty of isolation pose obstacles to their study in humans. Particularly, how diverse TEC lineages arise from a common progenitor remains poorly understood. To address this, here we establish a human iPSC-based model of thymus organogenesis capable of deriving these lineages in vitro. Through controlled retinoid signaling followed by self-directed differentiation, we obtain FOXN1⁺ TEC progenitor-like cells and diverse mature MHCII⁺ populations resembling cortical and medullary TECs, allowing us to infer their developmental trajectories. Upon thymocyte co-culture, induced TECs support the generation of naïve T cells with diverse TCR repertoires and further develop into AIRE ⁺ and mimetic TEC subpopulations. Our system provides a fully in vitro model of human TEC differentiation from early fate specification to late-stage maturation, offering new insights into human thymus development and potential regenerative applications for congenital thymic disorders.