SLF2 and SMC5 dysfunction drives HSC aging and predisposes to MDS, defining a new inherited bone marrow failure syndrome [ATAC-seq]

However, its clinical relevance to hematology has not yet been established, and the underlying pathogenic mechanisms remain largely unknown. Prompted by our longitudinal follow-up and re-evaluation revealing that some patients with Atelis Syndrome developed myelodysplastic syndromes (MDS) or MDS-like features, we elucidated the hematopoietic defects using hematopoietic stem and progenitor cells (HSPCs) derived from patient-specific induced pluripotent stem cells carrying compound heterozygous SLF2 mutations (mutant HSPCs) and gene-corrected isogenic controls.

Mutant HSPCs exhibited impaired colony-forming capacity and defective erythroid differentiation with a myeloid bias. Crucially, in vivo xenotransplantation revealed that mutant HSPCs had significantly reduced long-term engraftment capacity. Knockdown of SMC5 in human cord blood CD34+ cells similarly impaired colony formation.