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It has been nearly half a century since angioimmunoblastic T-cell lymphoma (AITL) was characterized in the early 1970’s. Our understanding of the disease has dramatically changed due to multiple discoveries and insights. One of the key features of AITL is aberrant immune activity. Although AITL is now understood to be a neoplastic disease, pathologists appreciated that it was an inflammatory condition. The more we understand AITL at cellular and genetic levels, the more we view it as both a neoplastic and an inflammatory disease. Here, we review recent progress in our understanding of AITL, focusing on as yet unsolved questions.

The term “clone” is commonly used in the medical and life sciences to denote a genetically identical population, at both the individual and cellular levels. The concept of clonal expansion is of fundamental importance in cancer research. The advent of advanced sequencing technologies has elucidated the clonal nature of intermediates between normal cells and cancer cells. This review underscores seminal discoveries in the blood and stratified squamous epithelial systems, emphasizing the pivotal role of mutations in DNA modifier genes and Notch pathway genes, respectively, as drivers of clonal expansion. Despite the distinct nature of these systems and their genetic backgrounds, a common biological principle emerges.

Haematopoietic stem cells (HSCs) are a rare cell type that reconstitute the entire blood and immune systems after transplantation and can be used as a curative cell therapy for a variety of haematological diseases 1 , 2 . However, the low number of HSCs in the body makes both biological analyses and clinical application difficult, and the limited extent to which human HSCs can be expanded ex vivo remains a substantial barrier to the wider and safer therapeutic use of HSC transplantation 3 . Although various reagents have been tested in attempts to stimulate the expansion of human HSCs, cytokines have long been thought to be essential for supporting HSCs ex vivo 4 . Here we report the establishment of a culture system that allows the long-term ex vivo expansion of human HSCs, achieved through the complete replacement of exogenous cytokines and albumin with chemical agonists and a caprolactam-based polymer. A phosphoinositide 3-kinase activator, in combination with a thrombopoietin-receptor agonist and the pyrimidoindole derivative UM171, were sufficient to stimulate the expansion of umbilical cord blood HSCs that are capable of serial engraftment in xenotransplantation assays. Ex vivo HSC expansion was further supported by split-clone transplantation assays and single-cell RNA-sequencing analysis. Our chemically defined expansion culture system will help to advance clinical HSC therapies. A culture system allows the long-term expansion of human haematopoietic stem cells (HSCs) in vivo without the use of recombinant cytokines or albumin, with potential applications for clinical therapies involving HSCs.

Immune cells harboring somatic mutations reportedly infiltrate cancer tissues in patients with solid cancers and accompanying clonal hematopoiesis. Loss‐of‐function TET2 mutations are frequently observed in clonal hematopoiesis in solid cancers. Here, using a mouse lung cancer model, we evaluated the activity of Tet2‐deficient immune cells in tumor tissues. Myeloid‐specific Tet2 deficiency enhanced tumor growth in mice relative to that seen in controls. Single‐cell sequencing analysis of immune cells infiltrating tumors showed relatively high expression of S100a8/S100a9 in Tet2‐deficient myeloid subclusters. In turn, treatment with S100a8/S100a9 promoted Vegfa production by cancer cells, leading to a marked increase in the tumor vasculature in Tet2‐deficient mice relative to controls. Finally, treatment of Tet2‐deficient mice with an antibody against Emmprin, a known S100a8/S100a9 receptor, suppressed tumor growth. These data suggest that immune cells derived from TET2‐mutated clonal hematopoiesis exacerbate lung cancer progression by promoting tumor angiogenesis and may provide a novel therapeutic target for lung cancer patients with TET2‐mutated clonal hematopoiesis. Our study suggests that immune cells derived from TET2‐mutated clonal hematopoiesis exacerbate lung cancer progression by promoting tumor angiogenesis. We present evidence that signaling through the S100a8/S100a9‐Emmprin‐Vegfa axis is essential for progression of a lung cancer model established in a microenvironment of Tet2‐deficient immune cells. Furthermore, we provide a novel target for lung cancer patients with accompanying TET2‐mutated clonal hematopoiesis.

We examined the associations between electroencephalogram (EEG)-based sleep characteristics and physical health parameters in general adults via a cross-sectional study recruiting 100 volunteers aged 30–59 years. Sleep characteristics were measured at home using a portable multichannel electroencephalography recorder. Using the k-means +  +  clustering method, according to 10 EEG-based parameters, participants were grouped into better (n = 39), middle (n = 46), and worse (n = 15) sleep groups. Comparing 50 physical health parameters among the groups, we identified four signals of difference (P < 0.05), including systolic (sBP) and diastolic blood pressure (dBP), γ-glutamyl transpeptidase (γ-GTP), and serum creatinine, where sBP reached a Bonferroni-corrected threshold (P < 0.001). The sBP was higher by 7.9 (95% confidence interval 1.9–13.9) and 15.7 (7.3–24.0) mmHg before adjustment and 5.4 (− 0.1–10.9) and 8.7 (1.1–16.3) mmHg after adjustment for age, sex, body mass index, smoking, drinking habits, and 3% oxygen desaturation index in the middle and worse sleep groups, respectively, than in the better group. As another approach, among 500 combinations of EEG-based and physical health parameters, there were 45 signals of correlation, of which 4 (N1% and sBP, dBP, γ-GTP, and triglycerides) reached a Bonferroni-corrected threshold (P < 0.0001). Thus, EEG-based sleep characteristics are associated with several physical health parameters, particularly sBP.

Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) is a diagnosis of exclusion, being the most common entity in mature T-cell neoplasms, and its molecular pathogenesis remains significantly understudied. Here, combining whole-exome and targeted-capture sequencing, gene-expression profiling, and immunohistochemical analysis of tumor samples from 133 cases, we have delineated the entire landscape of somatic alterations, and discovered frequently affected driver pathways in PTCL, NOS, with and without a T-follicular helper (TFH) cell phenotype. In addition to previously reported mutational targets, we identified a number of novel recurrently altered genes, such as KMT2C , SETD1B , YTHDF2 , and PDCD1 . We integrated these genetic drivers using hierarchical clustering and identified a previously undescribed molecular subtype characterized by TP53 and/or CDKN2A mutations and deletions in non-TFH PTCL, NOS. This subtype exhibited different prognosis and unique genetic features associated with extensive chromosomal instability, which preferentially affected molecules involved in immune escape and transcriptional regulation, such as HLA-A/B and IKZF2 . Taken together, our findings provide novel insights into the molecular pathogenesis of PTCL, NOS by highlighting their genetic heterogeneity. These results should help to devise a novel molecular classification of PTCLs and to exploit a new therapeutic strategy for this group of aggressive malignancies.

The activities of non-haematopoietic cells (NHCs), including mesenchymal stromal cells and endothelial cells, in lymphomas are reported to underlie lymphomagenesis. However, our understanding of lymphoma NHCs has been hampered by unexplained NHC heterogeneity, even in normal human lymph nodes (LNs). Here we constructed a single-cell transcriptome atlas of more than 100,000 NHCs collected from 27 human samples, including LNs and various nodal lymphomas, and it revealed 30 distinct subclusters, including some that were previously unrecognized. Notably, this atlas was useful for comparative analyses with lymphoma NHCs, which revealed an unanticipated landscape of subcluster-specific changes in gene expression and interaction with malignant cells in follicular lymphoma NHCs. This facilitates our understanding of stromal remodelling in lymphoma and highlights potential clinical biomarkers. Our study largely updates NHC taxonomy in human LNs and analysis of disease status, and provides a rich resource and deeper insights into LN and lymphoma biology to advance lymphoma management and therapy. Abe et al. profile, characterize and compare non-haematopoietic cells in normal human lymph nodes versus nodal lymphomas from patients, providing insights into stromal modelling in health and disease.

Foxp3+ regulatory T cells (Treg cells) modulate the immune system and maintain self-tolerance, but whether they affect haematopoiesis or haematopoietic stem cell (HSC)-mediated reconstitution after transplantation is unclear. Here we show that B-cell lymphopoiesis is impaired in Treg-depleted mice, yet this reduced B-cell lymphopoiesis is rescued by adoptive transfer of affected HSCs or bone marrow cells into Treg-competent recipients. B-cell reconstitution is abrogated in both syngeneic and allogeneic transplantation using Treg-depleted mice as recipients. Treg cells can control physiological IL-7 production that is indispensable for normal B-cell lymphopoiesis and is mainly sustained by a subpopulation of ICAM1+ perivascular stromal cells. Our study demonstrates that Treg cells are important for B-cell differentiation from HSCs by maintaining immunological homoeostasis in the bone marrow microenvironment, both in physiological conditions and after bone marrow transplantation.

Abnormal behaviors during sleep (ABDS) exhibit a myriad of symptoms. Their underlying diseases are also diverse, which include NREM/REM-related parasomnias, epilepsy and mental disorders. Since ABDS may severely affect a patient’s quality of life, giving an early and accurate diagnosis of the underlying disease (by analyzing video-polysomnographic data during the manifestation of ABDS) is of great importance. However, accurate diagnosis of ABDS is rather difficult. Recently it has been suggested that the pathology of (NREM/REM-related) parasomnias and epilepsy are closely related. In order to unravel the pathophysiological substrate of ABDS, it is essential to develop a novel approach based on sleep epileptology, a field which targets the interface between sleep medicine and epileptology.

Recent sequencing studies demonstrated the MYD88 L265P mutation in more than 70% of primary central nervous system lymphomas (PCNSL), and the clinical significance of this mutation has been proposed as diagnostic and prognostic markers in PCNSL. In contrast, mutational analyses using cell‐free DNAs have been reported in a variety of systemic lymphomas. To investigate how sensitively the MYD88 L265P mutation can be identified in cell‐free DNA from PCNSL patients, we carried out droplet digital PCR (ddPCR) and targeted deep sequencing (TDS) in 14 consecutive PCNSL patients from whom paired tumor‐derived DNA and cell‐free DNA was available at diagnosis. The MYD88 L265P mutation was found in tumor‐derived DNA from all 14 patients (14/14, 100%). In contrast, among 14 cell‐free DNAs evaluated by ddPCR (14/14) and TDS (13/14), the MYD88 L265P mutation was detected in eight out of 14 (ddPCR) and in 0 out of 13 (TDS) samples, implying dependence on the detection method. After chemotherapy, the MYD88 L265P mutation in cell‐free DNAs was traced in five patients; unexpectedly, the mutations disappeared after chemotherapy was given, and they remained undetectable in all patients. These observations suggest that ddPCR can sensitively detect the MYD88 L265P mutation in cell‐free DNA and could be used as non‐invasive diagnostics, but may not be applicable for monitoring minimal residual diseases in PCNSL. Our findings might provide new perspectives on the utility of ddPCR‐based detection of L265P MyD88 mutations in cell‐free DNAs as a non‐invasive diagnostic marker of PCNSL.