Single-cell profiling of human bone marrow progenitors reveals mechanisms of failing erythropoiesis in Diamond-Blackfan anemia

Abstract

Ribosome dysfunction underlies the pathogenesis of many cancers and heritable ribosomopathies. Here, we investigate how mutations in either ribosomal protein large (RPL) or ribosomal protein small (RPS) subunit genes selectively affect erythroid progenitor development and clinical phenotypes in Diamond-Blackfan anemia (DBA), a rare ribosomopathy with limited therapeutic options. Using single-cell assays of patient-derived bone marrow, we delineated two distinct cellular trajectories segregating with ribosomal protein genotypes. Almost complete loss of erythroid specification was observed in RPS-DBA. In contrast, we observed relative preservation of qualitatively abnormal erythroid progenitors and precursors in RPL-DBA. Although both DBA genotypes exhibited a proinflammatory bone marrow milieu, RPS-DBA was characterized by erythroid differentiation arrest, whereas RPL-DBA was characterized by preserved GATA1 expression and activity. Compensatory stress erythropoiesis in RPL-DBA exhibited disordered differentiation underpinned by an altered glucocorticoid molecular signature, including reduced ZFP36L2 expression, leading to milder anemia and improved corticosteroid response. This integrative analysis approach identified distinct pathways of erythroid failure and defined genotype-phenotype correlations in DBA. These findings may help facilitate therapeutic target discovery.

Arginine-dependent hypusination of the eukaryotic translation initiation factor (eIF)5A drives erythroid lineage differentiation

“…S5F ). Thus, while there is a large literature showing the specific importance of protein synthesis during erythropoiesis (Iskander et al, 2021; Khajuria et al, 2018; Vatikioti et al, 2019), our results highlight the importance of the cytoplasmic hypusine-dependent synthesis of the mitochondrial translation apparatus and thus, mitochondrial translation in erythroid differentiation.…”

Systems medicine dissection of chr1q-amp reveals a novel PBX1-FOXM1 axis for targeted therapy in multiple myeloma

“…Mononuclear cells from normal donor peripheral blood were isolated by Ficoll-Hypaque (Sigma-Aldrich) density centrifugation following the manufacturer's instructions, as described before 26 . The mononuclear cell interphase layer was aspirated, washed with 1ml PBS, centrifuged at 300g for 5min and resuspended in 100μl PBS.…”

Effect of Glucocorticosteroids in Diamond-Blackfan Anaemia: Maybe Not as Elusive as It Seems

“…Recent findings have suggested that erythropoiesis failure in DBA is more complicated than previously thought. More specifically, it seems that GATA1 impairment plays a crucial role in the DBA phenotype but only in ribosomal proteins of small-(RPS) and not large (RPL) subunit-related disorders [43].…”

“…Furthermore, it seems that stress erythropoiesis impairment plays a crucial role mainly in RPL-related DBA, and its external stimulation by GC treatment may result in restoration of this pathway [43].…”