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Blood Sep 2020Congenital dyserythropoietic anemias (CDAs) are a heterogeneous group of inherited anemias that affect the normal differentiation-proliferation pathways of the erythroid... (Review)
Review
Congenital dyserythropoietic anemias (CDAs) are a heterogeneous group of inherited anemias that affect the normal differentiation-proliferation pathways of the erythroid lineage. They belong to the wide group of ineffective erythropoiesis conditions that mainly result in monolinear cytopenia. CDAs are classified into the 3 major types (I, II, III), plus the transcription factor-related CDAs, and the CDA variants, on the basis of the distinctive morphological, clinical, and genetic features. Next-generation sequencing has revolutionized the field of diagnosis of and research into CDAs, with reduced time to diagnosis, and ameliorated differential diagnosis in terms of identification of new causative/modifier genes and polygenic conditions. The main improvements regarding CDAs have been in the study of iron metabolism in CDAII. The erythroblast-derived hormone erythroferrone specifically inhibits hepcidin production, and its role in the mediation of hepatic iron overload has been dissected out. We discuss here the most recent advances in this field regarding the molecular genetics and pathogenic mechanisms of CDAs, through an analysis of the clinical and molecular classifications, and the complications and clinical management of patients. We summarize also the main cellular and animal models developed to date and the possible future therapies.
Topics: Anemia, Dyserythropoietic, Congenital; Animals; Blood Transfusion; Diagnosis, Differential; Disease Models, Animal; Genetic Heterogeneity; Glycoproteins; Hematopoietic Stem Cell Transplantation; Hepcidins; High-Throughput Nucleotide Sequencing; Humans; Hydrops Fetalis; Iron Overload; Kruppel-Like Transcription Factors; Mice; Mice, Knockout; Microtubule-Associated Proteins; Molecular Diagnostic Techniques; Nuclear Proteins; Peptide Hormones; Vesicular Transport Proteins; Zebrafish
PubMed: 32702750
DOI: 10.1182/blood.2019000948 -
Journal of Cellular Physiology Jul 2021Erythroferrone (ERFE) is the main erythroid regulator of hepcidin, the homeostatic hormone controlling plasma iron levels and total body iron. When the release of... (Review)
Review
Erythroferrone (ERFE) is the main erythroid regulator of hepcidin, the homeostatic hormone controlling plasma iron levels and total body iron. When the release of erythropoietin from the kidney stimulates the production of new red blood cells, it also increases the synthesis of ERFE in bone marrow erythroblasts. Increased ERFE then suppresses hepcidin synthesis, thereby mobilizing cellular iron stores for use in heme and hemoglobin synthesis. Recent mechanistic studies have shown that ERFE suppresses hepcidin transcription by inhibiting bone morphogenetic protein signaling in hepatocytes. In ineffective erythropoiesis, pathological overproduction of ERFE by an expanded population of erythroblasts suppresses hepcidin and causes iron overload, even in non-transfused patients. ERFE may be a useful biomarker of ineffective erythropoiesis and an attractive target for treating its systemic effects.
Topics: Bone Morphogenetic Proteins; Erythroblasts; Erythropoiesis; Hepcidins; Homeostasis; Humans; Iron; Iron Overload; Peptide Hormones; Protein Conformation; Signal Transduction
PubMed: 33372284
DOI: 10.1002/jcp.30247 -
American Journal of Hematology Mar 2021Ring sideroblasts (RS) are erythroid precursors with abnormal perinuclear mitochondrial iron accumulation. Two myeloid neoplasms defined by the presence of RS, include... (Review)
Review
Myelodysplastic syndromes with ring sideroblasts (MDS-RS) and MDS/myeloproliferative neoplasm with RS and thrombocytosis (MDS/MPN-RS-T) - "2021 update on diagnosis, risk-stratification, and management".
DISEASE OVERVIEW
Ring sideroblasts (RS) are erythroid precursors with abnormal perinuclear mitochondrial iron accumulation. Two myeloid neoplasms defined by the presence of RS, include myelodysplastic syndromes with RS (MDS-RS) and MDS/myeloproliferative neoplasm with RS and thrombocytosis (MDS/MPN-RS-T).
DIAGNOSIS
MDS-RS is a lower risk MDS, with single or multilineage dysplasia (MDS-RS-SLD/MLD), <5% bone marrow (BM) blasts, <1% peripheral blood blasts and ≥15% BM RS (≥5% in the presence of SF3B1 mutations). MDS/MPN-RS-T, now a formal entity in the MDS/MPN overlap syndromes, has diagnostic features of MDS-RS-SLD, along with a platelet count ≥450 × 10 /L and large atypical megakaryocytes.
MUTATIONS AND KARYOTYPE
Mutations in SF3B1 are seen in ≥80% of patients with MDS-RS-SLD and MDS/MPN-RS-T, and strongly correlate with the presence of BM RS; MDS/MPN-RS-T patients also demonstrate JAK2V617F (50%), DNMT3A, TET2 and ASXL1 mutations. Cytogenetic abnormalities are uncommon in both.
RISK STRATIFICATION
Most patients with MDS-RS-SLD are stratified into lower risk groups by the revised-IPSS. Disease outcome in MDS/MPN-RS-T is better than that of MDS-RS-SLD, but worse than that of essential thrombocythemia (MPN). Both diseases are associated with a low risk of leukemic transformation.
TREATMENT
Anemia and iron overload are complications seen in both and are managed similar to lower risk MDS and MPN. Luspatercept, a first-in-class erythroid maturation agent is now approved for the management of anemia in patients with MDS-RS and MDS/MPN-RS-T. Aspirin therapy is reasonable in MDS/MPN-RS-T, especially in the presence of JAK2V617F, but the value of platelet-lowering drugs remains to be defined.
Topics: Allografts; Anemia, Sideroblastic; Bone Marrow; Cell Lineage; Clone Cells; Combined Modality Therapy; DNA Methylation; Disease Management; Erythroblasts; Ferritins; Hematinics; Hematopoietic Stem Cell Transplantation; Humans; Iron Chelating Agents; Mitochondria; Mutation; Myelodysplastic-Myeloproliferative Diseases; Phosphoproteins; Prognosis; RNA Splicing Factors; Risk Assessment; Thrombocytosis
PubMed: 33428785
DOI: 10.1002/ajh.26090 -
Cell Aug 2021Emerging evidence supports that mitochondrial dysfunction contributes to systemic lupus erythematosus (SLE) pathogenesis. Here we show that programmed mitochondrial...
Emerging evidence supports that mitochondrial dysfunction contributes to systemic lupus erythematosus (SLE) pathogenesis. Here we show that programmed mitochondrial removal, a hallmark of mammalian erythropoiesis, is defective in SLE. Specifically, we demonstrate that during human erythroid cell maturation, a hypoxia-inducible factor (HIF)-mediated metabolic switch is responsible for the activation of the ubiquitin-proteasome system (UPS), which precedes and is necessary for the autophagic removal of mitochondria. A defect in this pathway leads to accumulation of red blood cells (RBCs) carrying mitochondria (Mito RBCs) in SLE patients and in correlation with disease activity. Antibody-mediated internalization of Mito RBCs induces type I interferon (IFN) production through activation of cGAS in macrophages. Accordingly, SLE patients carrying both Mito RBCs and opsonizing antibodies display the highest levels of blood IFN-stimulated gene (ISG) signatures, a distinctive feature of SLE.
Topics: Adolescent; Basic Helix-Loop-Helix Transcription Factors; Child; Child, Preschool; Erythroblasts; Erythrocytes; Erythropoiesis; Humans; Interferon Type I; Lupus Erythematosus, Systemic; Mitochondria; Mitophagy; Myeloid Cells; Proteasome Endopeptidase Complex; Ubiquitin
PubMed: 34384544
DOI: 10.1016/j.cell.2021.07.021 -
Blood Oct 2022The erythroblastic island (EBI), composed of a central macrophage surrounded by maturing erythroblasts, is the erythroid precursor niche. Despite numerous studies, its...
The erythroblastic island (EBI), composed of a central macrophage surrounded by maturing erythroblasts, is the erythroid precursor niche. Despite numerous studies, its precise composition is still unclear. Using multispectral imaging flow cytometry, in vitro island reconstitution, and single-cell RNA sequencing of adult mouse bone marrow (BM) EBI-component cells enriched by gradient sedimentation, we present evidence that the CD11b+ cells present in the EBIs are neutrophil precursors specifically associated with BM EBI macrophages, indicating that erythro-(myelo)-blastic islands are a site for terminal granulopoiesis and erythropoiesis. We further demonstrate that the balance between these dominant and terminal differentiation programs is dynamically regulated within this BM niche by pathophysiological states that favor granulopoiesis during anemia of inflammation and favor erythropoiesis after erythropoietin stimulation. Finally, by molecular profiling, we reveal the heterogeneity of EBI macrophages by cellular indexing of transcriptome and epitope sequencing of mouse BM EBIs at baseline and after erythropoietin stimulation in vivo and provide a searchable online viewer of these data characterizing the macrophage subsets serving as hematopoietic niches. Taken together, our findings demonstrate that EBIs serve a dual role as niches for terminal erythropoiesis and granulopoiesis and the central macrophages adapt to optimize production of red blood cells or neutrophils.
Topics: Animals; Mice; Epitopes; Erythroblasts; Erythropoiesis; Erythropoietin
PubMed: 35862735
DOI: 10.1182/blood.2022015724 -
Cell Stem Cell Aug 2022Reprogramming somatic cells into megakaryocytes (MKs) would provide a promising source of platelets. However, using a pharmacological approach to generate human MKs from...
Reprogramming somatic cells into megakaryocytes (MKs) would provide a promising source of platelets. However, using a pharmacological approach to generate human MKs from somatic cells remains an unmet challenge. Here, we report that a combination of four small molecules (4M) successfully converted human cord blood erythroblasts (EBs) into induced MKs (iMKs). The iMKs could produce proplatelets and release functional platelets, functionally resembling natural MKs. Reprogramming trajectory analysis revealed an efficient cell fate conversion of EBs into iMKs by 4M via the intermediate state of bipotent precursors. 4M induced chromatin remodeling and drove the transition of transcription factor (TF) regulatory network from key erythroid TFs to essential TFs for megakaryopoiesis, including FLI1 and MEIS1. These results demonstrate that the chemical reprogramming of cord blood EBs into iMKs provides a simple and efficient approach to generate MKs and platelets for clinical applications.
Topics: Blood Platelets; Cell Differentiation; Erythroblasts; Fetal Blood; Humans; Megakaryocytes
PubMed: 35931032
DOI: 10.1016/j.stem.2022.07.004 -
Cell Reports. Medicine May 2023Erythroblastic islands (EBIs) are the specialized structures for erythropoiesis, but they have never been found functional in tumors. As the most common pediatric liver...
Erythroblastic islands (EBIs) are the specialized structures for erythropoiesis, but they have never been found functional in tumors. As the most common pediatric liver malignancy, hepatoblastoma (HB) requires more effective and safer therapies to prevent progression and the lifelong impact of complications on young children. However, developing such therapies is impeded by a lack of comprehensive understanding of the tumor microenvironment. By single-cell RNA sequencing of 13 treatment-naive HB patients, we discover an immune landscape characterized by aberrant accumulation of EBIs, formed by VCAM1 macrophages and erythroid cells, which is inversely correlated with survival of HB. Erythroid cells inhibit the function of dendritic cells (DCs) via the LGALS9/TIM3 axis, leading to impaired anti-tumor T cell immune responses. Encouragingly, TIM3 blockades relieve the inhibitory effect of erythroid cells on DCs. Our study provides an immune evasion mechanism mediated by intratumoral EBIs and proposes TIM3 as a promising therapeutic target for HB.
Topics: Child; Humans; Child, Preschool; Erythroblasts; Hepatoblastoma; Hepatitis A Virus Cellular Receptor 2; Erythropoiesis; Liver Neoplasms; Tumor Microenvironment
PubMed: 37196629
DOI: 10.1016/j.xcrm.2023.101044 -
American Journal of Hematology Jun 2022
Topics: Erythroblasts; Erythropoiesis; Humans
PubMed: 34826173
DOI: 10.1002/ajh.26425