Clinical implications of RAS mutations in AML: prognostic significance is based upon the involved gene and mutation complexity

Colgan JN, Peplinski JH, Wang YC, Kirkey DC, Wallace LK, Feng Y, Fan L, Connerty P, Ries RE, Lamble A, Huang BJ, Alonzo TA, Ma X, Tarlock K, Meshinchi S. Clinical implications of RAS mutations in AML: prognostic significance is based upon the involved gene and mutation complexity. Blood Adv. 2026 Jul 14;10(13):4814-4827. doi: 10.1182/bloodadvances.2025018699. PMID: 42118855; PMCID: PMC13352172.

Acute myeloid leukemia (AML) is a heterogeneous disease with complex mutational profiles that lead to variable clinical outcomes. NRAS and KRAS are among the most frequently mutated genes in AML, but their clinical impact has not been well characterized. In this cohort of >2000 children and young adults with AML, we evaluated the role of mutations in RAS genes and mutation complexity in outcome determination. Given enrichment in KMT2A-rearranged (KMT2A-r) AML, we specifically studied the significance of RAS mutations in KMT2A-r AML. Using variant calls from next-generation sequencing platforms, we identified RAS mutations in 35.1% (N = 669; NRAS, n = 518; KRAS, n = 216). We demonstrated that NRAS mutations were not associated with outcome in AML or in KMT2A-r AML. In contrast, KRAS mutations demonstrated inferior outcomes in AML, with enrichment of prevalence and enhancement of prognostic implications in KMT2A-r AML, including non–high-risk KMT2A fusions. Additionally, we describe a complex RAS (Comp-RAS) mutation cohort characterized by 2 distinct RAS mutations or high variant allele frequency RAS mutations that collectively account for 13.5% (n = 90) of the patients with RAS mutations. Patients with complex KRAS mutations and those with Comp-RAS mutations in the KMT2A-r cohort had a distinctly adverse outcome, and data demonstrate that Comp-RAS status drives adverse outcomes for those with KRAS mutations in the whole AML cohort.