Genetic Heterogeneity of Cytogenetically Normal AML with Mutations of

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