Gene mutations behind serious bone marrow conditions identified

Inherited bone marrow failure syndrome, or IBMFS, describes a group of disorders in which inherited genetic abnormalities impair the bone marrow’s ability to produce sufficient healthy blood cells. Patients with these disorders are also at increased risk of developing myelodysplastic syndromes—MDS—a group of blood cancers in which the bone marrow produces excess abnormal blood cells and insufficient healthy ones.

When young patients are diagnosed with either condition, an underlying germline genetic abnormality can generally be suspected as the cause. The genetic basis and mechanisms of these diseases remain unknown in many patients, but advances in genomic analysis are identifying an increasing number of causative genes.

Recently, germline variants in the genes SLF2 and SMC5 were reported to cause Atelis syndrome, a neurodevelopmental disorder frequently accompanied by blood abnormalities. During a follow-up of patients with the syndrome, a team of researchers at Kyoto University found that some had developed MDS at a young age and that clinical features of IBMFS were evident. The team hypothesized that abnormalities in SLF2 and SMC5 represent a previously unrecognized cause of IBMFS and indicate a predisposition to MDS.

The scientists established iPS cell lines from a patient carrying pathogenic SLF2 variants and used these to generate genetically corrected isogenic lines with CRISPR-Cas9 gene editing. They then differentiated the hematopoietic progenitor cells, which produce mature blood cells, and evaluated the effects of the SLF2 variants on hematopoietic stem cell function both in vitro and in vivo.

The team’s results confirm that germline mutations in SLF2 and SMC5 cause both IBMFS and a predisposition to MDS. Furthermore, these mutations induce activation of the cancer-fighting p53 protein and lead to premature hematopoietic stem cell aging. The research is published in the Leukemia journal.

“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,” says first author Sho Shibata.

These findings identify the causative genes behind IBMFS and germline predisposition to MDS and provide new insights into how defects in SLF2 and SMC5 promote hematopoietic stem cell aging. The results also give researchers clues for identifying the genetic causes of unexplained IBMFS and MDS in 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,” says corresponding author Kazuhisa Chonabayashi. “We hope these findings will improve our understanding of previously unexplained cases and pave the way for new therapeutic strategies.”

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Gaby Clark

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Robert Egan

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