Authors
Eduardo Rodríguez-Arbolí, Elena Soria-Saldise, Eva Barragan, Rosa Ayala, Joaquin Sánchez-García, Cristina Bilbao-Sieyro, M Carmen Chillon, María José Larrayoz, Paulina Hillebrand, Teresa Bernal Del Castillo, Juan Miguel Bergua Burgues, Carmen Botella, Mar Tormo, Lorenzo Algarra, Rafael Colmenares, Josefina Serrano, María García-Fortes, Amaia Balerdi, Juan Manuel Alonso-Domínguez, Carlos Rodríguez-Medina, Maria Jose García Perez, Lourdes Hermosín, Irene Sanchez Vadillo, Rosa Fernández Martín, Ana Oliva Hernandez, Raimundo García-Boyero, Francisco Ibañez-Alis, Mercedes Colorado, José-Ángel Raposo-Puglia, Carolina Lacalzada Higueras, Víctor Noriega, Pilar Herrera, Aitor Abuin Blanco, María Solé-Rodríguez, María-Belén Vidriales, Jorge Labrador, Lara María Gómez-García, María Del Carmen García Garay, Juan A Lopez-Lopez, Olga Arce-Fernández, Teresa Olave, Esther Pérez Santaolalla, Claudia Sargas, Joaquin Martínez-López, Esther Prados de la Torre, Maria Teresa Gomez Casares, Norma C Gutierrez, Maria José Calasanz, José Antonio Pérez-Simón, Pau Montesinos
Published in
Blood. Oct 16, 2026. Epub Oct 16, 2026.
Abstract
RAS mutations are recurrent in acute myeloid leukemia (AML); yet, their genomic and clinical landscape remain poorly characterized. We analyzed centralized molecular profiling data in 8,553 patients with newly diagnosed AML. Of these, 1,775 (21%) harbored RAS mutations: NRAS in 1,103 (13%), KRAS in 445 (5%), and both in 227 (3%). RAS mutations primarily clustered in P-loop hotspots (G12/G13, 70%), with NRAS showing higher Q61 mutation prevalence (24% vs. 9%) and KRAS showing additional K117/A146 hotspots. Multiple RAS mutations occurred in 23% of patients. Convergent evolution of RAS signaling mutations emerged as a key feature of RASmut AML. RTK/RAS pathway mutations were non-uniformly enriched: PTPN11, KIT and FLT3-TKD mutations were positively associated, CBL mutations showed no association, and FLT3-ITD mutations were negatively associated. The prognostic impact of RAS mutations was dependent on the genomic background and treatment. In multivariate analyses in intensively treated patients, NRAS mutations showed opposing associations with overall survival (OS): adverse in patients with AML, myelodysplasia-related (HR=1.32, p=0.036) and favorable in those with NPM1 (HR=0.61, p=0.036) or FLT3-ITD (HR=0.63, p=0.048) mutations, among others. KRAS mutations predicted inferior OS (HR=1.41; p=0.003). In patients treated with non-intensive, venetoclax-based regimens, RAS mutations were associated with markedly inferior OS in patients with NPM1 (HR=2.98, p=0.007) or IDH1/2 mutations (HR=4.06, p<0.001). These data inform risk stratification and development of RAS-targeting strategies in AML.
PMID:
42886676
Bibliographic data and abstract were imported from PubMed on 17 Oct 2026.
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