Highlights d SMARCB1-deficient human iPSCs give rise to AT/RT-like tumors d ESC-like signature induces rhabdoid histology and causes a poor prognosis d AT/RT exhibits ESC-like transcriptional signature and DNA methylation landscape d ESC-like signature could be a therapeutic target for AT/RT
Clear cell sarcoma (CCS) is a rare soft tissue sarcoma caused by the EWS/ATF1 fusion gene. Here, we established induced pluripotent stem cells (iPSCs) from
EWS/ATF1
-controllable murine CCS cells harboring sarcoma-associated genetic abnormalities. Sarcoma-iPSC mice develop secondary sarcomas immediately after EWS/ATF1 induction, but only in soft tissue.
EWS/ATF1
expression induces oncogene-induced senescence in most cell types in sarcoma-iPSC mice but prevents it in sarcoma cells. We identify
Tppp3
-expressing cells in peripheral nerves as a cell-of-origin for these sarcomas. We show cell type-specific recruitment of EWS/ATF1 to enhancer regions in CCS cells. Finally, epigenetic silencing at these enhancers induces senescence and inhibits CCS cell growth through altered EWS/ATF1 binding. Together, we propose that distinct responses to premature senescence are the basis for the cell type-specificity of cancer development.
Age is a major risk factor for COVID-19 severity, and T cells play a central role in anti-SARS-CoV-2 immunity. Because SARS-CoV-2-cross-reactive T cells have been detected in unexposed individuals, we investigated the age-related differences in pre-existing SARS-CoV-2-reactive T cells. SARS-CoV-2-reactive CD4+ T cells from young and elderly individuals were mainly detected in the central memory fraction and exhibited similar functionalities and numbers. Naïve-phenotype SARS-CoV-2-reactive CD8+ T cell populations decreased markedly in the elderly, while those with terminally differentiated and senescent phenotypes increased. Furthermore, senescent SARS-CoV-2-reactive CD8+ T cell populations were higher in cytomegalovirus seropositive young individuals compared to seronegative ones. Our findings suggest that age-related differences in pre-existing SARS-CoV-2-reactive CD8+ T cells may explain the poor outcomes in elderly patients and that cytomegalovirus infection is a potential factor affecting CD8+ T cell immunity against SARS-CoV-2. Thus, this study provides insights for developing effective therapeutic and vaccination strategies for the elderly.
Whether age-associated defects in T cells impact the immunogenicity and reactogenicity of mRNA vaccines remains unclear. Using a vaccinated cohort (n = 216), we demonstrated that older adults (aged ≥65 years) had fewer vaccine-induced spike-specific CD4+ T cells including CXCR3+ circulating follicular helper T cells and the TH1 subset of helper T cells after the first dose, which correlated with their lower peak IgG levels and fewer systemic adverse effects after the second dose, compared with younger adults. Moreover, spike-specific TH1 cells in older adults expressed higher levels of programmed cell death protein 1, a negative regulator of T cell activation, which was associated with low spike-specific CD8+ T cell responses. Thus, an inefficient CD4+ T cell response after the first dose may reduce the production of helper T cytokines, even after the second dose, thereby lowering humoral and cellular immunity and reducing systemic reactogenicity. Therefore, enhancing CD4+ T cell response following the first dose is key to improving vaccine efficacy in older adults.
High disease burden in myeloablative allogeneic hematopoietic stem cell transplantation is associated with adverse outcomes in patients with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). Quiescent leukemia stem cells could be induced to enter cell cycle by granulocyte colony-stimulating factor (G-CSF) administration and become more susceptible to chemotherapy. We report on the outcome of unrelated cord blood transplantation (CBT) using a conditioning regimen of 12 Gy total body irradiation, G-CSF-combined high-dose cytarabine, and cyclophosphamide in 61 adult patients with AML or advanced MDS not in remission. With a median follow-up of 97 months, the probability of overall survival and cumulative incidence of relapse at 7 years were 61.4% and 30.5%, respectively. In multivariate analysis, poor-risk cytogenetics and high lactate dehydrogenase values at CBT were independently associated with inferior survival. These data demonstrate that CBT after G-CSF-combined myeloablative conditioning is a promising curative option for patients with myeloid malignancies not in remission.
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