Bi-directional association between RUNX1::RUNX1T1 and KIT mutations in acute myeloid leukemia: A multicenter genomic profiling study.

Next-generation sequencing has delineated recurrent genomic lesions in acute myeloid leukemia (AML), with mutations in some genes exhibiting prognostic relevance. Studies have reported that KIT mutations may confer an adverse risk in AML with RUNX1::RUNX1T1. However, in real-world practice, the bi-directional relationship between RUNX1::RUNX1T1 and KIT mutations and the impact on outcome remains insufficiently defined. We analyzed 331 AML patients enrolled in two multicenter genomic profiling studies in Japan (HMS-01 and HMS-02) to clarify the bi-directional association between RUNX1::RUNX1T1 and KIT mutations. RUNX1::RUNX1T1 was detected in 25 cases (7.6%) and KIT mutations in 18 cases (5.4%). Ten patients (3.0% of the total AML group) harbored both RUNX1::RUNX1T1 and KIT mutations, representing 40% of AML with RUNX1::RUNX1T1 and 56% of KIT-mutated AML; all co-occurring KIT mutations were located in exon 17 and most cases were enrolled at relapse or in refractory disease. In AML with RUNX1::RUNX1T1, common co-mutations included KIT (40%), FLT3 (12%), and NRAS (12%), and RUNX1::RUNX1T1 was the most frequent fusion in KIT-mutated AML. The median overall survival was 35.1 months for AML with RUNX1::RUNX1T1 versus 24.0 months for other AML (p = 0.0797) and 28.1 months in patients with KIT mutations versus 25.6 months in those without (p = 0.9051). These data highlight a strong biological association between RUNX1::RUNX1T1 and KIT exon 17 mutations and underscore the need for prospectively designed studies and the evaluation of KIT-directed therapeutic strategies in this subset of patients with AML.