Genetic heterogeneity of cytogenetically normal AML with mutations of CEBPA

Biallelic mutations of the CCAAT/enhancer binding protein α ( CEBPA ) gene define a distinct genetic entity of acute myeloid leukemia (AML) with favorable prognosis. The presence of GATA2 and CSF3R mutations that are specifically associated with this subgroup but not mutated in all samples suggests a genetic heterogeneity of bi CEBPA -mutated AML. We characterized the mutational landscape of CEBPA -mutated cytogenetically normal AML by targeted amplicon resequencing. We analyzed 48 biallelically mutated CEBPA (bi CEBPA ), 32 monoallelically mutated CEBPA (mo CEBPA ), and 287 wild-type CEBPA (wt CEBPA ) patient samples from German AML Cooperative Group studies or registry. Targeted sequencing of 42 genes revealed that mo CEBPA patients had significantly more additional mutations and additional mutated genes than bi CEBPA patients. Within the group of bi CEBPA patients, we identified 2 genetic subgroups defined by the presence or absence of mutations in chromatin/DNA modifiers (C), cohesin complex (C), and splicing (S) genes: bi CEBPA CCSpos (25/48 [52%]) and bi CEBPA CCSneg (23/48 [48%]). Equivalent subgroups were identified in 51 bi CEBPA patients from the Cancer Genome Project. Patients in the bi CEBPA CCSpos group were significantly older and had poorer overall survival and lower complete remission rates following intensive chemotherapy regimens compared with patients in the bi CEBPA CCSneg group. Patients with available remission samples from the bi CEBPA CCSpos group cleared the bi CEBPA mutations, but most had persisting CCS mutations in complete remission, suggesting the presence of a preleukemic clone. In conclusion, CCS mutations define a distinct biological subgroup of bi CEBPA AML that might refine prognostic classification of AML. This trial was registered at www.clinicaltrials.gov as #NCT00266136 and NCT01382147.