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

ABSTRACT: Pathogenic variants in SLF2 and SMC5 cause a developmental disorder known as Atelis Syndrome, characterized by microcephaly, short stature, and hematological abnormalities, most notably anemia and lymphopenia. 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. Mechanistically, disruption of the SLF2–SMC5 axis induces increased genomic instability, p53/p21 activation, and transcriptional signatures of senescence. Furthermore, ATAC sequencing uncovered epigenetic features of hematopoietic stem cell (HSC) aging, including increased accessibility at PU.1 motifs, driving myeloid bias. In conclusion, we establish that SLF2 and SMC5 dysfunction drives premature HSC aging and predisposes to MDS, defining Atelis Syndrome as a distinct entity within the inherited bone marrow failure syndromes (IBMFS). These findings highlight the need to incorporate Atelis Syndrome into the diagnostic framework of IBMFS, improving genetic diagnosis and guiding clinical management of hematological abnormalities.

ORGANISM(S): Homo sapiens

PROVIDER: GSE316079 | GEO | 2026/08/06

REPOSITORIES: GEO