Mutations in the CCAAT/enhancer binding protein alpha (CEBPA) are detected in about 10% of patients with cytogenetically normal acute myeloid leukemia (CN-AML). CEBPA mutation can either affect both CEBPA alleles (biallelic, biCEBPA) or only one allele (monoallelic, moCEBPA). We and others have shown that only patients with biCEBPA mutations have favorable outcomes when compared to other CN-AML patients (Dufour et al, JCO 2009; Green et al, JCO, 2010). Interestingly, biCEBPA mutations are rarely associated with other known prognostic mutations (e.g. FLT3-ITD, NPM1).
In this study we aimed to characterize the mutational spectrum of CN-AML patients with mo- and biCEBPA mutations using a targeted amplicon sequencing approach. We analyzed 45 biCEBPA patients and 35 moCEBPA patients. 55 of these patients (26 biCEBPA and 29 moCEBPA) were enrolled in a multicenter trial of the German AML Cooperative Group (AMLCG-1999).
Our amplicon resequencing panel included 42 genes which are known to be frequently mutated in AML (Haloplex, target region 62 kilobases). Out of these 42 genes we identified 23 different mutated genes in the biCEBPA subgroup and a total of 28 different mutated genes in the moCEBPA cohort. The mean number of mutated genes per moCEBPA patient was significantly larger (4.37±1.6) than in biCEBPA patients (2.96±1.22) (P<0.05). The two groups also differed remarkably with regard to the genes that were mutated. In the moCEBPA group FLT3 (46%), NPM1 (46%), TET2 (37%) and DNMT3A (26%) were the most frequently mutated genes, whereas the biCEBPA group showed frequent mutations in TET2 (40%), GATA2 (36%) and FLT3 (18%). Thus there was a strong association of NPM1 (P<0.0001), FLT3 (P=0.01) and IDH2 (P=0.04) mutations with the moCEBPA group. GATA2 mutations were significantly associated with biCEBPA mutations (P=0.0003). NPM1 and biCEBPA mutations were mutually exclusive.
In this large and well characterized CEBPA-mutated patient cohort we identified distinct mutational landscapes in patients with moCEBPA and biCEBPA mutated CN-AML. The lower number of mutated genes within the biCEBPA group suggests that biallelic CEBPA mutations may act as a strong driver. In almost all cases, patients with biallelic mutations of CEBPA have a C-terminal mutation in one allele of CEBPA and an N-terminal mutation in the other allele. These date provide further insight into the genetic background of CEBPA mutated CN-AML. We are currently analyzing the prognostic impact of the associated mutations.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.