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However, the mechanism underlying the hematopoietic failure remained unknown, and treatment options are limited. Herein, we investigated the onset of SDS embryonic hematopoietic impairments. We generated SDS and control human\u2010derived induced pluripotent stem cells (iPSCs). SDS iPSCs recapitulated the SDS hematological phenotype. Detailed stepwise evaluation of definitive hematopoiesis revealed defects that started at the early emerging hematopoietic progenitor (EHP) stage after mesoderm and hemogenic\u00a0endothelium were normally induced. Hematopoietic potential of EHPs was markedly reduced, and the introduction of <jats:italic>SBDS<\/jats:italic> in SDS iPSCs improved colony formation. Transcriptome analysis revealed reduced expression of ribosome and oxidative phosphorylation\u2010related genes in undifferentiated and differentiated iPSCs. However, certain pathways (e.g., DNA replication) and genes (e.g., <jats:italic>CHCHD2<\/jats:italic>) were exclusively or more severely dysregulated in EHPs compared with earlier and later stages. To our knowledge, this study offers for the first time an insight into the embryonic onset of human hematopoietic defects in an inherited bone marrow failure syndrome and reveals cellular and molecular aberrations at critical stages of hematopoietic development toward EHPs.<\/jats:p>","DOI":"10.1111\/ejh.14260","type":"journal-article","created":{"date-parts":[[2024,7,5]],"date-time":"2024-07-05T15:40:08Z","timestamp":1720194008000},"page":"530-542","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Aberrant early hematopoietic progenitor formation marks the onset of hematopoietic defects in Shwachman\u2013Diamond syndrome"],"prefix":"10.1111","volume":"113","author":[{"given":"Alejandra","family":"Lagos\u2010Monzon","sequence":"first","affiliation":[{"name":"Genetics and Genome Biology, Research Institute The Hospital for Sick Children  Toronto Ontario Canada"},{"name":"Institute of Medical Science, Faculty of 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