ダイアモンド・ブラックファン貧血

Defects in ribosome biogenesis cause ribosomopathies, but the pathogenic role of malformed preribosomes remains unclear. Using preribosome fractionation, live-cell and confocal microscopy, and automated imaging screens, we tracked abortive preribosomes following depletion of the 33 small-subunit ribosomal proteins (RPSs). We found that all RPS deficiencies lead to accumulation of nucleolar preribosome materials in the nucleoplasm, regardless of the affected 40S subunit maturation stage. These aberrant particles appear as dispersed complexes or persistent aggregates arising during nucleolar reassembly in late mitosis. Although nucleolar morphology remains largely intact, their accumulation impairs recycling of nucleolar factors and disrupts nucleolar-nucleoplasmic proteostasis. Distinct RPS deficiencies produce different preribosome behaviors, indicating maturation-specific properties. Notably, depletion of RPS19, the protein encoded by the most frequently mutated gene in Diamond-Blackfan anemia, causes particularly severe defects. Our findings identify nucleoplasmic preribosome aggregation and dispersion as common consequences of RPS deficits and potential contributors to 40S ribosomopathy pathogenesis.

Gene therapy is revolutionizing treatment paradigms for inherited haematological and immunological conditions. Recent successes, including the United States Food and Drug Administration (FDA) approval of gene therapy products for sickle cell disease and beta-thalassaemia, highlight the translational path of gene therapies for erythroid-specific disorders. In contrast, gene therapy development for other inherited erythroid disorders remains largely preclinical. Here, we examine the emerging landscape of gene therapies for inherited non-haemoglobinopathy erythroid disorders, focusing on the status of gene therapies for Diamond-Blackfan anaemia (DBA), pyruvate kinase deficiency (PKD), X-linked sideroblastic anaemia (XLSA), congenital erythropoietic porphyria (CEP) and congenital dyserythropoietic anaemia (CDA). We discuss the latest cellular engineering approaches being applied to developing therapies for these erythroid disorders and evolving strategies for conditioning and engraftment of modified cells. Despite the rarity of these disorders individually, several convergent biological and translational themes have emerged. Leveraging shared insights across diseases may accelerate clinical translation and broaden the curative potential of gene therapy for inherited erythroid disorders beyond the haemoglobinopathies.

Diamond-Blackfan anemia (DBA) is a classic example of an inherited bone marrow failure syndrome in the category of erythrocyte diseases. DBA mainly occurs due to ribosome dysfunction. In the peripheral blood, reticulocytes are reduced, and in the bone marrow, only erythroid cells are markedly reduced. DBA primarily develops in infants and is often caused by heterozygous allele mutations in ribosomal protein genes. Activation of p53, translation dysfunction, inflammatory signals, and imbalance of hemoglobin/heme synthesis have been shown to contribute to impaired erythropoiesis and decreased red blood cell production. Patients with DBA are primarily treated with steroids; however, half of these patients eventually become unresponsive to long-term steroid treatment and become transfusion-dependent. Hematopoietic cell transplantation is currently the only curative treatment. Recent advances in gene therapy using lentiviral vectors have shown potential in promoting normal hematopoiesis in the treatment of RPS19-deficient DBA.

Ribosomes are central to cellular growth and proteome maintenance, and cancer cells frequently depend on increased ribosome biogenesis and altered translation to sustain proliferation, stress tolerance, and metabolic rewiring. Paradoxically, inherited "ribosomopathies" caused by germline defects in ribosomal proteins or ribosome biogenesis factors present with tissue hypoplasia and bone marrow failure early in life, yet confer substantially increased lifetime risk of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and selected solid tumors. In parallel, somatic alterations affecting ribosomal proteins and ribosome regulatory pathways recur across malignancies, including hematologic cancers such as T-cell acute lymphoblastic leukemia (T-ALL), and in pediatric solid tumors. Mechanistically, oncogenic ribosome disturbances can reprogram translation toward specific mRNA subsets, alter translational fidelity, trigger nucleolar/ribosomal stress signaling via the 5S ribonucleoprotein (5S RNP)-MDM2-p53 axis, and enable selection for compensatory or cooperating lesions (notably TP53 pathway alterations). Clinically, these insights support diagnostics and surveillance of inherited ribosome-related cancer predisposition syndromes, therapeutic targeting of ribosome biogenesis and translational control, including RNA polymerase I inhibition, and the eIF4 translation-initiation machinery. Here, we present current evidence linking constitutional and acquired ribosomal dysfunction to leukemogenesis and tumorigenesis, highlight disease- and context-specific mechanisms, and outline priorities for translational research and precision therapy.