Genomic and clinical landscape of RAS mutations in acute myeloid leukemia

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.

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Journal
Blood
Published
2026-10-16
DOI
https://doi.org/10.1182/blood.2026033409
Primary Topic
Acute Myeloid Leukemia Research
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article
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article

Genomic and clinical landscape of RAS mutations in acute myeloid leukemia

Pau Montesinos, Esther Prados de la Torre, Mar Tormo, Elena Soria‐Saldise et al.
Blood
Acute Myeloid Leukemia Research
article

Genomic and clinical landscape of RAS mutations in acute myeloid leukemia

Pau Montesinos, Esther Prados de la Torre, Mar Tormo, Elena Soria‐Saldise, Eva Barragán, José Ángel Raposo-Puglia, Irene Sánchez Vadillo, Lourdes Hermosín, Juan Manuel Alonso‐Domínguez, Jorge Labrador, Claudia Sargas, Lorenzo Algarra, Joaquín Martínez‐López, María José García-Pérez, María José Larráyoz, Norma Carmen Gutierrez, Josefina Serrano, Pilar Herrera, Maria Carmen García Garay, Mercedes Colorado, Raimundo García‐Boyero, Eduardo Rodríguez‐Arbolí, Amaia Balerdi, Lara M. Gómez García, Cristina Bilbao, Juan Bergua, María‐Belén Vídriales, Víctor Noriega, María Solé‐Rodríguez, Teresa Bernal, Juan A. López-López, Carmen Chillón, María Teresa Gómez‐Casares, Carmen Botella, Joaquín Sánchez‐García, María García‐Fortes, Josè Antonio Pérez-Simón, Marı́a José Calasanz, Rafael Colmenares, Aitor Abuín Blanco, María Teresa Olave, Paulina Hillebrand, Ana Oliva Hernández, Olga Arce, Carlos Rodríguez‐Medina, Esther Pérez‐Santaolalla, Rosa Fernandez Martin, Francisco Ibañez, Rosa Ayala, Carolina Lacalzada Higueras
article en

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.

Blood
Consejo Superior de Investigaciones Científicas (ES), Universidad de Salamanca (ES), Hospital Universitario Insular de Gran Canaria (ES), Hospital Universitario de Canarias (ES), Hospital Universitario La Paz (ES), Princess Margaret Cancer Centre (CA), Hospital Universitari i Politècnic La Fe (ES), Research Institute Hospital 12 de Octubre (ES), Hospital Universitario Nuestra Señora de Candelaria (ES), Hospital de Basurto (ES), Instituto Maimónides de Investigación Biomédica de Córdoba (ES), Complejo Hospitalario Universitario de Santiago (ES), Hospital Universitario de Gran Canaria Doctor Negrín (ES), Marqués de Valdecilla University Hospital (ES), Hospital Universitario 12 De Octubre (ES), Hospital San Pedro de Alcántara (ES), Hospital Universitario de Burgos (ES), Complejo Hospitalario de Jaén (ES), Hospital Universitario Reina Sofía (ES), Hospital General Universitari de Castelló (ES), Hospital General Universitario De Valencia (ES), Hospital Juan Ramón Jiménez (ES), Instituto de Biomedicina de Sevilla (ES), Hospital Universitario Central de Asturias (ES), Instituto de Investigación Biomédica de Salamanca (ES), Clinica Universidad de Navarra (ES), Hospital Clínico Universitario Lozano Blesa (ES), Hospital de Cruces (ES), Hospital General Universitario de Alicante Doctor Balmis (ES), Centro de Investigación del Cáncer (ES), Donostiako Unibertsitate Ospitalea (ES), Complexo Hospitalario Universitario A Coruña (ES), Hospital Universitario Puerta del Mar (ES), Hospital General Universitario de Albacete (ES), Hospital Universitario Virgen de la Arrixaca (ES), Complejo Hospitalario Torrecárdenas (ES), Hospital Universitario Virgen del Rocío (ES), Hospital Jerez Puerta del Sur (ES), Hospital Clínico Universitario Virgen de la Victoria (ES), Hospital Clínico Universitario de Valladolid (ES), INCLIVA Health Research Institute (ES), Hospital Universitario Ramón y Cajal (ES), Instituto de Investigación Sanitaria La Fe (ES), Instituto de Investigación Sanitaria del Principado de Asturias (ES), Instituto de Biología Molecular y Celular del Cáncer de Salamanca, Hospital Universitario de Jerez (ES), University of Córdoba (ES), Universidad de Sevilla (ES), Universidad de Navarra (ES)
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