Potential factors underlying the progression of RUNX1-mutated MDS to AML

This study explores the molecular distinctions between myelodysplastic neoplasms (MDS) and acute myeloid leukemia (AML) with RUNX1 mutations (RUNX1mut), aiming to elucidate factors influencing the progression from MDS to AML. Analyzing 1520 patients (773 AML and 747 MDS cases), RUNX1mut were present in 10 % of MDS and 13 % of AML cases. Interestingly, RUNX1mut were associated with higher blast counts in MDS, suggesting a potential role in disease progression. Despite similar overall survival across subgroups, significant differences in variant allele frequency (VAF) were observed, correlating with blast count. Our study highlights a unique genetic signature in both RUNX1mut MDS and AML: Cytogenetic analysis showed a higher frequency of normal karyotypes in RUNX1mut-MDS compared to RUNX1mut-AML. While only trisomy 8 was found in MDS, trisomies 8, 11, and 13 were detected in RUNX1mut-AML. Notably, MECOM rearrangements, KMT2A-PTD, and FLT3-ITD alterations were exclusive to RUNX1mut-AML. RUNX1 mutations were strongly associated with spliceosome gene mutations, especially in RUNX1mut-MDS. Copy neutral loss of heterozygosity (CN-LOH) involving RUNX1 was detected in 22 % of RUNX1mut-AML cases but was absent in RUNX1mut-MDS. These findings highlight the distinct genetic landscape of RUNX1mut-MDS and AML. Understanding these molecular determinants may enhance monitoring and early intervention strategies for MDS patients at risk of progression to AML.