Acute Myeloid Leukemia with Deletion 9q Is Associated with CEBPA Loss-of-Function Mutations.

The transcription factor CCAAT/enhancer binding protein alpha (C/EBPalpha) plays an important role in the development of mature neutrophils. Two common types of mutations in the CEBPA gene encoding C/EBPalpha have been identified in approximately 10% of adults with acute myeloid leukemia (AML): N-terminal, dominant-negative frameshift mutations that result in loss of C/EBPalpha function and C-terminal in-frame mutations that result in C/EBPalpha proteins with decreased DNA-binding potential. Previous studies concluded that mutant CEBPA predicts favorable outcome in younger AML patients with intermediate-risk karyotypes or normal cytogenetics. To assess the prevalence of CEBPA mutations in specific cytogenetic subgroups, mutational analysis of the CEBPA gene was performed in 125 AML patients. No CEBPA mutations were detected in 77 patients with t(8;21), inv(16)/t(16;16), t(15;17), or balanced translocations with breakpoints in band 11q23. In 58 patients with various non-complex karyotypic abnormalities, CEBPA mutations were present in 8 (14%). Surprisingly, 5 of the 8 patients with del(9q) as the sole aberration or in combination with a single additional abnormality other than t(8;21) had CEBPA mutations associated with loss of C/EBPalpha function. Consequently, 41 additional del(9q) cases were analyzed; 9 had CEBPA loss-of-function mutations. The overall prevalence of CEBPA loss-of-function mutations in cases with del(9q) within a non-complex karyotype was 41% (14 of 34 patients), whereas none of the patients who had a del(9q) within a complex karyotype (n = 7), in combination with a t(8;21) (n = 10), or together with a t(15;17) (n = 1) demonstrated mutant CEBPA. Analysis of associated mutations indicated that alterations of the FLT3, MLL, and NRAS genes are not common cooperating events in the pathogenesis of del(9q) AML with inactivating CEBPA mutations. This is the first study to show that AML with del(9q) is strongly associated with CEBPA loss-of-function mutations. The coincidence of del(9q) with inactivating CEBPA mutations and the fact that del(9q) is a common secondary cytogenetic abnormality in t(8;21)-positive AML, that is characterized by specific down-regulation of CEBPA, raise the possibility that loss of a critical segment of 9q, most likely in 9q22, and disruption of C/EBPalpha function cooperate in the pathogenesis of these leukemias. Further refinement of the commonly deleted segment of 9q using high-resolution techniques is underway to identify the critical gene(s) involved and their role in normal hematopoiesis and leukemogenesis. A collaborative intergroup study has been initiated to define whether the relatively good prognosis associated with del(9q) is related to the presence of a CEBPA mutation.