Gene mutations linked to bone marrow failure and early blood cancer risk

A team at Kyoto University has identified germline mutations in the genes SLF2 and SMC5 as a previously unrecognized cause of inherited bone marrow failure syndrome (IBMFS) and a predisposition to myelodysplastic syndromes (MDS), a group of blood cancers. The findings were published in the journal Leukemia.

IBMFS refers to disorders in which inherited genetic abnormalities impair the bone marrow's ability to produce sufficient healthy blood cells. Patients with these conditions also face an increased risk of developing MDS, in which the marrow produces excess abnormal cells and too few healthy ones. The genetic basis remains unknown for many patients.

The researchers began by following up on patients with Atelis syndrome, a neurodevelopmental disorder linked to variants in SLF2 and SMC5 that is frequently accompanied by blood abnormalities. They observed that some young patients had developed MDS and showed clinical features of IBMFS, suggesting the genes might play a role in hematopoietic stem cell maintenance.

To test this, the scientists established induced pluripotent stem cell (iPSC) lines from a patient carrying pathogenic SLF2 variants. Using CRISPR-Cas9 gene editing, they created genetically corrected isogenic lines and differentiated both into hematopoietic progenitor cells. They then evaluated stem cell function in vitro and in vivo.

The experiments confirmed that germline mutations in SLF2 and SMC5 cause both IBMFS and a predisposition to MDS. The mutations trigger activation of the p53 protein, a key cancer-fighting factor, and lead to premature aging of hematopoietic stem cells, impairing their ability to sustain blood production.

Correcting the SLF2 variants in the patient-derived iPSCs reversed the cellular abnormalities, providing direct evidence that the variants drive bone marrow failure. The researchers say the results offer new clues for diagnosing unexplained cases of IBMFS and MDS in young patients and may inform future therapeutic strategies.