Ibáñez, MariamCarbonell-Caballero, JoséSuch, EsperanzaGarcía-Alonso, LuzLiquori, AlessandroLópez-Pavía, MaríaLlop, MartaAlonso, CarmenBarragán, EvaGómez-Seguí, InésNeef, AlexanderHervás, DavidMontesinos, PauSanz, GuillermoSanz, Miguel AngelDopazo, JoaquínCervera, José2023-01-252023-01-252018-10-10http://hdl.handle.net/10668/13054Acute myeloid leukemia (AML) is associated with the sequential accumulation of acquired genetic alterations. Although at diagnosis cytogenetic alterations are frequent in AML, roughly 50% of patients present an apparently normal karyotype (NK), leading to a highly heterogeneous prognosis. Due to this significant heterogeneity, it has been suggested that different molecular mechanisms may trigger the disease with diverse prognostic implications. We performed whole-exome sequencing (WES) of tumor-normal matched samples of de novo AML-NK patients lacking mutations in NPM1, CEBPA or FLT3-ITD to identify new gene mutations with potential prognostic and therapeutic relevance to patients with AML. Novel candidate-genes, together with others previously described, were targeted resequenced in an independent cohort of 100 de novo AML patients classified in the cytogenetic intermediate-risk (IR) category. A mean of 4.89 mutations per sample were detected in 73 genes, 35 of which were mutated in more than one patient. After a network enrichment analysis, we defined a single in silico model and established a set of seed-genes that may trigger leukemogenesis in patients with normal karyotype. The high heterogeneity of gene mutations observed in AML patients suggested that a specific alteration could not be as essential as the interaction of deregulated pathways.enAttribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/AdultAgedCytodiagnosisFemaleGene Regulatory NetworksGenetic Association StudiesGenetic HeterogeneityHumansKaryotypeLeukemia, Myeloid, AcuteMaleMiddle AgedMutationNeoplasm ProteinsNucleophosminPrognosisExome Sequencingresearch article30303964open access10.1371/journal.pone.02029261932-6203PMC6179200https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0202926&type=printablehttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC6179200/pdf