Comprehensive Analysis of Genetic Alterations in Acute Myeloid Leukemia According to the WHO Classification.

Acute myeloid leukemia (AML) is a heterogeneous clonal disorder of hematopoietic progenitor cells, and is thought to be the consequence of two broad complementation classes of mutations: those that confer a proliferative and/or survival advantage to hematopoietic progenitors, and those that impair hematopoietic differentiation and confer properties of self-renewal. To date, several genetic alterations, which are involved in the pathophysiology of the AML development, have been apparent, and some of them have been disclosed to have an impact on the clinical management. Therefore, it is required to establish the detailed classification of AML according to the genetic status. In this study, we comprehensively analyzed the genetic alterations in AML patients in comparison with the WHO classification. The study population included 115 newly diagnosed AML patients consisting of 25 recurrent genetic abnormalities, 25 multilineage dysplasia, 7 therapy-related and 56 not otherwise categorized WHO subcategories. Bone marrow samples were obtained from the patients after obtaining informed consent for banking and molecular analyses. Mutations in FLT3, cKIT, NPM1, N-RAS, p53, C/EBPa, AML1 and AKT1 genes were analyzed as previously described. In consistent with previous reports, FLT3 (20.9%), NPM1 (14.8%) and C/EBPa (13.0%) mutations were frequently observed, while no AKT1 mutation was found. Furthermore, NPM1 mutation was not found in AML with recurrent genetic abnormalities and C/EBPa mutation was not found in AML with recurrent genetic abnormalities or therapy related. Nine cases have double mutations of FLT3 and NPM1 genes, and 3 have FLT3 and C/EBPa mutations. Of note is that 15 of 25 (60%) AML with multilineage dysplasia cases have at least one mutation in p53, NPM1, C/EBPa, FLT3, N-RAS and AML1 genes and that p53 mutation was selectively found in the cases with complex karyotype. However, 4 AML with multilineage dysplasia cases with normal karyotype did not have any mutations in the analyzed genes. Comprehensive genetic analysis clarifies the detailed molecular base of AML and could make the subdivision of the WHO classification by combining the analysis for clinical impacts. Especially, mutation status in p53, NPM1 and C/EBPa genes seems to be useful for the subdivision of the AML with multilineage dysplasia, which is the most heterogeneous subcategory in the WHO classification.