Abstract
Acute myeloid leukemia (AML) is a heterogeneous disorder of hematopoietic progenitor cells. The World Health Organization (WHO) classification of the myeloid neoplasm incorporates genetic, immunophenotypic, biologic and clinical features. Although the WHO classification recognizes several chromosomal translocations they are frequently seen in AML patients, for categorizing the AML with recurrent genetic abnormalities, a number of other genetic alterations such as point mutations and gene rearrangements have not been included. To date, several genetic alterations, which are involved in the pathogenesis of AML and associated with prognosis of patients, have been documented. 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 and in de nove AML patients and investigated the association with mutational status, cytogenetic status and clinical features in comparison with the WHO classification. The study population included 144 newly diagnosed de nove AML patients consisting of 38 recurrent genetic abnormalities (RGA), 34 multilineage dysplasia (MLD) and 72 not otherwise categorized (NOC) according to 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, TP53, C/EBPA, AML1, WT1 and MLL/PTD were analyzed as previously described. In consistent with previous reports, FLT3 (24%), cKIT (5%), NPM1 (20%), N-RAS (8%), C/EBPA (12%), AML1 (2%), MLL-PTD (9%), WT1 (3%) and TP53 (8%) mutations were frequently observed. No significantly different distribution was found in the prevalence of FLT3, N-RAS, C/EBPA, AML1 and MLL-PTD mutations among the WHO categories. However, the skewed prevalence was found in cKIT, NPM1 and TP53 mutations: cKIT mutation was frequently found in AML-RGA, NPM1 mutation was not found in AML-RGA, and TP53 mutation was preferentially found in AML-MLD. N-RAS, C/EBPA, AML1 and WT1 mutations were not identified in AML-RGA, though their distributions were not statistically significant among the WHO categories. It is notable that 9 of 12 (75%) patients who have TP53 mutation are categorized in AML with MLD and 8 of the 9 have complex-karyotype. Importantly, 8 of 9 (88.9%) showed complex karyotype, and 5 of them deleted chromosome 17. In this study, we found 2 additional patients harboring TP53 mutation in the other categories, while they did not show the complex karyotype and chromosome 17 abnormality. Furthermore, complex karyotype was found in 14 of the 144 entire AML patients, while 10 of them were categorized in AML-MLD. The remaining 4 patients were categorized in AML-NOC. Three of them showed del(17) or del(17p), though TP53 mutation was not identified. The genotype consisting of complex karyotype and TP53 mutation was, therefore, specifically found in AML-MLD. Thus TP53 mutation and complex-karyotype AML are significantly correlated and associated with the presence of multi-lineage dysplasia (P= .000 and P= .000, respectively). Moreover, these patients have significantly inferior induction rate and overall survival in AML with MLD. These results suggest that TP53 mutation and complex-karyotype AML distinguish a disease entity in AML with MLD.
How to unmask unique vulnerabilities in leukaemia