In AML Secondary to MDS NPM1 Mutations Are Late Events, Less Frequent, and Associated with a Different Pattern of Molecular Mutations Than in De Novo AML

Autor: Wolfgang Kern, Karolína Perglerová, Susanne Schnittger, Manja Meggendorfer, Tamara Alpermann, Claudia Haferlach, Torsten Haferlach, Niroshan Nadarajah
Rok vydání: 2014
Předmět:
Zdroj: Web of Science
ISSN: 1528-0020
0006-4971
Popis: Background: NPM1 mutations (mut) are considered the most frequent mutations in de novo acute myeloid leukemia (AML) and have been suggested as provisional entity in the WHO classification 2008. It has become clear that nearly all NPM1mut AML have additional mutations that may contribute to onset of AML by affecting different genetic pathways. However, it has not been evaluated yet whether the pattern of additional mutations varies between NPM1mut de novo AML and NPM1mut secondary AML (sAML) arising from a previous myelodysplastic syndrome (MDS). Aim: To evaluate the 1) genetic pattern associated with NPM1mut de novo AML and sAML, 2) chronologic sequence of mutations from MDS to sAML. Patients and Methods: 5,545 de novo AML and 504 sAML cases were analyzed during the last 9 years. The de novo cohort was comprised of 2,951 males and 2,594 females, median age was 65.7 years (y; range 17.5-93.1 y). The sAML cohort was comprised of 329 males and 175 females, median age was 71.7 y (range 29.3-91.8 y; p=0.004). All cases were analyzed for NPM1mut by a melting curve analysis. For more detailed analysis from these cohorts 359 NPM1mut de novo AML (162 male, 197 female; median age: 61.4 y, range: 17.8-88.0 y), and 21 sAML (12 male, 9 female; median age: 70.3 y, range: 44.2-87.4 y) were selected for mutation analysis in 13 different genes (ASXL1, CEBPA, DNMT3A, FLT3-ITD, FLT3-TKD, IDH1, IDH2, KRAS, MLL-PTD, NRAS, RUNX1, TET2, TP53, WT1). Paired samples from the diagnostic time points of both MDS and sAML, respectively, were available in all 21 sAML cases. For both time points an NPM1-specific quantitative real time PCR was performed in addition. Results: First the overall frequency of NPM1mut was calculated from the total cohort. NPM1mut was more frequent in de novo AML (1,737/5,545 cases; 31.2%) than in sAML (67/504; 13.3%) (p Conclusions: NPM1 mutations 1) occur less frequent in sAML than in de novo AML, 2) like FLT3mut are usually late events that drive transformation from MDS to sAML, 3) are frequently associated with TET2, ASXL1 and RUNX1 mutations in sAML whereas in de novo AML most frequently are accompanied by DNMT3A mutations. Disclosures Schnittger: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Nadarajah:MLL Munich Leukemia Laboratory: Employment. Alpermann:MLL Munich Leukemia Laboratory: Employment. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Perglerová:MLL2 s.r.o.: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.
Databáze: OpenAIRE
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