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SLF2 and SMC5 dysfunction drives HSC aging and predisposes to MDS, defining a new inherited bone marrow failure

Sho Shibata1,2, Kazuhisa Chonabayashi3,4, Hirofumi Nakamura2

  • 1Department of Hematology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.

Leukemia
|August 7, 2026
PubMed

Insights

Atelis Syndrome, caused by SLF2 and SMC5 gene mutations, leads to premature aging of hematopoietic stem cells (HSCs), resulting in bone marrow failure and myelodysplastic syndromes (MDS). This discovery identifies Atelis Syndrome as a novel inherited bone marrow failure syndrome (IBMFS).

Area of Science:

  • Genetics and Hematology
  • Stem Cell Biology
  • Genomic Instability and Aging

Background:

  • Inherited bone marrow failure syndromes (IBMFS) are genetic disorders increasing myelodysplastic syndromes (MDS) risk.
  • Atelis Syndrome, linked to SLF2 and SMC5 variants, causes neurodevelopmental and hematological issues, but mechanisms are unclear.
  • Some Atelis Syndrome patients develop early-onset MDS, necessitating investigation into hematopoietic dysfunction.

Purpose of the Study:

  • To elucidate the mechanisms underlying hematopoietic dysfunction in Atelis Syndrome.
  • To investigate the role of SLF2-SMC5 axis disruption in hematopoietic stem cell (HSC) defects and MDS predisposition.
  • To characterize the cellular and molecular consequences of SLF2 mutations in patient-derived cells.

Main Methods:

  • Analysis of patient-derived induced pluripotent stem cells (iPSCs) and their hematopoietic progenitor cells (HPCs) with compound heterozygous SLF2 mutations.
  • Xenotransplantation assays using mutant HPCs to assess engraftment potential.
  • SMC5 knockdown in human cord blood CD34+ cells.
  • ATAC sequencing to analyze epigenetic modifications in HPCs.

Main Results:

  • Mutant HPCs showed impaired colony formation, defective erythroid differentiation with myeloid bias, and reduced xenotransplantation engraftment.
  • SLF2-SMC5 axis disruption induced genomic instability, p53/p21 activation, and a senescence-like phenotype.
  • ATAC sequencing revealed HSC aging signatures, including altered chromatin accessibility at PU.1 motifs, correlating with myeloid bias.

Conclusions:

  • SLF2 and SMC5 dysfunction drives premature HSC aging, leading to bone marrow failure.
  • This dysfunction predisposes individuals to early-onset myelodysplastic syndromes (MDS).
  • Atelis Syndrome is identified as a previously unrecognized inherited bone marrow failure syndrome (IBMFS).

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