{"doi":"10.17169/refubium-29068","title":"Consequences of ribosomal perturbations in human hematopoiesis","abstract":"Hematopoiesis, the formation of blood cells, is probably the best understood system of cellular differentiation in mammalian biology. Traditionally, this process is thought to occur as a hierarchical progression of differentiation from hematopoietic stem cells (HSCs), where progressively lineage restricted oligo-, bi-, and unipotent progenitors are generated, eventually producing mature blood cells. However, this classical view is based on analyses performed in marker pre-defined bulk cell populations and has been challenged. Recent studies, enabled by single cell technologies, suggest that lineage commitment in hematopoiesis occurs much earlier than previously thought, at the hematopoietic stem and progenitor cell (HSPC) stage. It remains unclear what relevance these refined models of hematopoiesis have with regard to human diseases. Furthermore, while tremendous insight has been gained into this process on the transcriptional level, the contribution of post-transcriptional regulation in hematopoiesis remains to be largely explored. Here, we use an experiment of nature, the rare congenital disorder Diamond-Blackfan anemia (DBA), where the majority of mutations affect ribosomal proteins and the erythroid lineage is selectively perturbed, as a model to address these issues. We use human genetics to gain deeper insight into the ribosomal defects in DBA in vivo, biochemical and proteomic studies to examine ribosome levels and composition in human hematopoietic cells with DBA-associated molecular lesions, ribosome profiling in HSPCs undergoing erythroid lineage commitment to assess changes in translation globally, transcriptome analyses of hematopoietic master regulators from unperturbed human HSPCs, and intracellular flow cytometry analyses of primary DBA patient samples to elucidate the pathological mechanisms underlying DBA and how these relate to physiologic lineage commitment. We find that in DBA, the cellular levels of ribosomes are reduced, while the ribosome protein composition remains unaltered. This global reduction of ribosome levels impairs the translation of a select subset of transcripts including the key erythroid transcription factor GATA1. These transcripts have, among other properties, shorter and less structured 5’ UTRs than unaffected mRNAs, features that GATA1 exhibits relatively uniquely among hematopoietic master regulators, which may explain the erythroid lineage selective defect in DBA. Finally, we show that GATA1 protein levels are reduced already at the HSPC stage in primary DBA patients’ bone marrow specimens, which fits to the refined models of hematopoiesis that suggest lineage commitment takes place in this primitive cell compartment. By studying the rare congenital disorder DBA, we gain insight into how cellular ribosome levels and translation play a key role in the process of human hematopoietic lineage commitment.","journal":"Refubium (Universitätsbibliothek der Freien Universität Berlin)","year":2021,"id":225634,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9572,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":98610,"name":"Rajiv K. Khajuria","orcid":null,"position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T23:54:30.292454Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}