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Blood Advances Sep 2023The anemias of myelodysplastic syndrome (MDS) and Diamond Blackfan anemia (DBA) are generally macrocytic and always reflect ineffective erythropoiesis yet result from...
The anemias of myelodysplastic syndrome (MDS) and Diamond Blackfan anemia (DBA) are generally macrocytic and always reflect ineffective erythropoiesis yet result from diverse genetic mutations. To delineate shared mechanisms that lead to cell death, we studied the fate of single erythroid marrow cells from individuals with DBA or MDS-5q. We defined an unhealthy (vs healthy) differentiation trajectory using transcriptional pseudotime and cell surface proteins. The pseudotime trajectories diverge immediately after cells upregulate transferrin receptor (CD71), import iron, and initiate heme synthesis, although cell death occurs much later. Cells destined to die express high levels of heme-responsive genes, including ribosomal protein and globin genes, whereas surviving cells downregulate heme synthesis and upregulate DNA damage response, hypoxia, and HIF1 pathways. Surprisingly, 24% ± 12% of cells from control subjects follow the unhealthy trajectory, implying that heme might serve as a rheostat directing cells to live or die. When heme synthesis was inhibited with succinylacetone, more DBA cells followed the healthy trajectory and survived. We also noted high numbers of messages with retained introns that increased as erythroid cells matured, confirmed the rapid cycling of colony forming unit-erythroid, and demonstrated that cell cycle timing is an invariant property of differentiation stage. Including unspliced RNA in pseudotime determinations allowed us to reliably align independent data sets and accurately query stage-specific transcriptomic changes. MDS-5q (unlike DBA) results from somatic mutation, so many normal (unmutated) erythroid cells persist. By independently tracking erythroid differentiation of cells with and without chromosome 5q deletions, we gained insight into why 5q+ cells cannot expand to prevent anemia.
Topics: Humans; Erythropoiesis; Transcriptome; Anemia; Ribosomal Proteins; Anemia, Diamond-Blackfan; Myelodysplastic Syndromes; Chromosome Deletion; Heme
PubMed: 37352261
DOI: 10.1182/bloodadvances.2023010382 -
Immunologic Research Dec 2023The effects of specific cytokines produced by T cell subsets (such as Th1, Th2, and newly discovered Th17, Treg, Tfh, or Th22) are diverse, depending on interactions...
The effects of specific cytokines produced by T cell subsets (such as Th1, Th2, and newly discovered Th17, Treg, Tfh, or Th22) are diverse, depending on interactions with other cytokines, distinct signaling pathways, phase of the disease, or etiological factor. The immunity equilibrium of the immune cells, such as the Th1/Th2, the Th17/Treg, and the Th17/Th1 balance is necessary for the maintenance of the immune homeostasis. If the balance of the T cells subsets is damaged, the autoimmune response becomes enhanced which leads to autoimmune diseases. Indeed, both the Th1/Th2 and the Th17/Treg dichotomies are involved in the pathomechanism of autoimmune diseases. The aim of the study was to determine the cytokines of Th17 lymphocytes as well as the factors modulating their activity in patients with pernicious anemia. The magnetic bead-based immunoassays used (Bio-Plex) allow simultaneous detection of multiple immune mediators from one serum sample. In our study, we showed that patients suffering from pernicious anemia develop the Th1/Th2 imbalance with a quantitative advantage of cytokines participating in Th1-related immune response, the Th17/Treg imbalance with a quantitative advantage of cytokines participating in Treg-related response, as well as the Th17/Th1 imbalance with a quantitative predominance of cytokines participating in Th1-related immune response. Our study results indicate that T lymphocytes and their specific cytokines play an role in the course of pernicious anemia. The observed changes may indicate the immune response to pernicious anemia or be an element of the pernicious anemia pathomechanism.
Topics: Humans; Cytokines; Anemia, Pernicious; T-Lymphocytes, Regulatory; Th17 Cells; Autoimmune Diseases; Th1 Cells; Th2 Cells
PubMed: 37269464
DOI: 10.1007/s12026-023-09399-9 -
Zeitschrift Fur Rheumatologie Apr 2024An adult-onset autoinflammatory syndrome caused by somatic mutations in the UBA1 gene on the X chromosome was first reported in 2020. This VEXAS syndrome (acronym for...
An adult-onset autoinflammatory syndrome caused by somatic mutations in the UBA1 gene on the X chromosome was first reported in 2020. This VEXAS syndrome (acronym for vacuoles, E1 enzyme, X‑linked, autoinflammatory, somatic) is characterized by an overlap of rheumatic inflammatory diseases with separate hematologic abnormalities. A substantial number of affected patients suffer from treatment refractory relapsing polychondritis and nearly always show signs of macrocytic anemia. This case report illustrates the diagnostic key points to recognizing patients with VEXAS syndrome.
Topics: Adult; Humans; Anemia, Macrocytic; Autoimmune Diseases; Polychondritis, Relapsing; Myelodysplastic Syndromes; Rheumatic Diseases; Mutation; Skin Diseases, Genetic
PubMed: 36735069
DOI: 10.1007/s00393-023-01318-5 -
Blood Advances Jul 2023GATA1 mutations that result in loss of the N-terminal 83 amino acids are a feature of myeloid leukemia in children with Down syndrome, rare familial cases of...
GATA1 mutations that result in loss of the N-terminal 83 amino acids are a feature of myeloid leukemia in children with Down syndrome, rare familial cases of dyserythropoietic anemia, and a subset of cases of Diamond-Blackfan anemia. The Gata1s mouse model, which expresses only the short GATA1 isoform that begins at methionine 84, has been shown to have a defect in hematopoiesis, especially impaired erythropoiesis with expanded megakaryopoiesis, during gestation. However, these mice reportedly did not show any postnatal phenotype. Here, we demonstrate that Gata1s mutant mice display macrocytic anemia and features of aberrant megakaryopoiesis throughout life, culminating in profound splenomegaly and bone marrow fibrosis. These data support the use of this animal model for studies of GATA1 deficiencies.
Topics: Animals; Mice; Cell Lineage; Down Syndrome; Erythropoiesis; Protein Isoforms; Thrombopoiesis
PubMed: 36350717
DOI: 10.1182/bloodadvances.2022008124