Key Points

  • Up to 30% of RUNX1 mutations in the Leucegene AML cohort were confirmed to be germline.

  • RUNX1 germline mutated AML show high frequency of NRAS mutations and other mutations known to activate various signaling pathways.

RUNX1 is mutated in approximately 10% of adult AML. Although most RUNX1 mutations in this disease are believed to be acquired, they can also be germline. Indeed, germline RUNX1 mutations result in the well-described autosomal dominant familial platelet disorder with predisposition to hematologic malignancies (RUNX1-FPD, FPD/AML, FPDMM) in which about 44% of affected individuals progress to AML or myelodysplastic syndromes. Using the Leucegene RUNX1 AML patient group, we sought to investigate the proportion of germline versus acquired RUNX1 mutations in this cohort. Our results showed that 30% of RUNX1 mutations in our AML cohort are germline. Molecular profiling revealed higher frequencies of NRAS mutations and other mutations known to activate various signaling pathways in these RUNX1 germline mutated AML. Moreover, two patients (mother and son) had co-occurrence of RUNX1 and CEBPA germline mutations with variable AML disease onset at 59 and 27 years, respectively. Together this data suggests a higher than anticipated frequency of germline RUNX1 mutations in the Leucegene cohort and further highlights the importance of testing for RUNX1 mutations in instances where allogeneic stem cell transplantation with related donor is envisioned.

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