A new study published on Aug. 6 reveals that germline mutations in the SLF2 and SMC5 genes are linked to inherited bone marrow failure syndrome (IBMFS) and a predisposition to myelodysplastic syndromes (MDS), a group of blood cancers. Researchers at Kyoto University investigated patients with Atelis Syndrome, a neurodevelopmental disorder associated with blood abnormalities, and found that some developed MDS at an early age, showing clinical features consistent with IBMFS.
The research team hypothesized that abnormalities in SLF2 and SMC5 represent previously unrecognized causes of IBMFS as well as indicators for increased MDS risk. Using induced pluripotent stem cell lines derived from a patient carrying pathogenic SLF2 variants, the scientists applied CRISPR-Cas9 gene editing to create genetically corrected isogenic lines. They then differentiated hematopoietic progenitor cells from these lines to assess how the SLF2 variants affected hematopoietic stem cell function both in laboratory settings and animal models.
The results confirmed that germline mutations in SLF2 and SMC5 cause both IBMFS and an increased likelihood of developing MDS. The study also found that these mutations activate the p53 protein—a key factor in cancer suppression—and accelerate aging in hematopoietic stem cells.
"We were intrigued to find that genes originally linked to a neurodevelopmental disorder also play a critical role in maintaining hematopoietic stem cell function and that their disruption predisposes individuals to MDS," said first author Sho Shibata.
According to the researchers, identifying these causative genes provides insight into how defects in SLF2 and SMC5 promote premature aging of blood-forming stem cells, offering clues for diagnosing unexplained cases of IBMFS or MDS among young patients. "It is particularly exciting to see that correcting the SLF2 variants in patient-derived iPSCs reversed the cellular abnormalities, providing direct evidence that these variants cause bone marrow failure," said corresponding author Kazuhisa Chonabayashi. "We hope these findings will improve our understanding of previously unexplained cases and pave the way for new therapeutic strategies."
