Transcription factor CCAAT/enhancer binding protein alpha (C/EBPα) is essential for granulocyte differentiation. CEBPα mutations have been described in 7–10% of patients with AML at initial diagnosis and was associated with a favorable prognosis. The role of CEBPα mutations in the progression of myeloid leukemias is not clearly defined. We sought to assess the role of CEBPα mutations in the progression of myeloid leukemias and to determine whether the mutation patterns during disease progression differed from those at initial diagnosis. CEBPα mutation status was evaluated by DNA polymerase chain reaction (PCR) followed by direct sequencing for each PCR product. CEBPα mutations were analyzed in 141 patients with de novo AML at both diagnosis and relapse, 21 (14.9%) patients had the mutations at diagnosis, 19 of them relapsed with identical patterns, 2 lost CEBPα mutations and none acquired the mutations at relapse. Nineteen of 21 patients had two CEBPα mutations occurring in both N-terminal part and bZIP domain of the protein, one had homozygous inframe duplication in the bZIP domain, and the remaining one had a heterozygous N-terminal frameshift mutation. Clonal analysis using expand long template PCR assay was performed to determine the allelic distribution in those who carrying two different mutations. The results showed that heterozygous biallelic mutations were present in all 18 patients examined; in addition, all but one had some cloned alleles harboring combined mutations in the same alleles. Nineteen of the 21 patients with CEBPα mutations had FAB subtypes of AML-M1 or M2. Cytogenetic analysis was performed in 15 of the 21 patients, all had intermediate cytogenetics. CEBPα mutations were detected in 4 of 50 patients with myelodysplastic syndrome (MDS) at initial diagnosis, including 1 of the 27 patients who had refractory anemia with excess blasts and 3 of the 15 patients who had chronic myelomonocytic leukemia. CEBPα mutations were not observed in any of the 8 patients who had refractory anemia with or without ringed sideroblasts. At time of AML transformation, 3 of 4 patients retained the identical mutated clones as their initial diagnosis of MDS, one lost CEBPα mutation, and another 3 acquired the mutations. Taken together, 7 patients had CEBPα mutations in their disease courses of MDS, N-terminal mutations were observed in 5 patients and mutations in the bZIP domain were found in 2 patients. None had mutations occurring in both N-terminal part and bZIP domain. Three patients had two different N-terminal mutations. Clonal analysis demonstrated that the two mutations occurred either in the same alleles or in different alleles. There was no significant difference in clinicohematological characteristics, IPSS score or outcome between patients with and without CEBPα mutations. CEBPα mutations were not detected in any of the 30 patients with myeloid blast crisis of chronic myeloid leukemia. The present results showed that 90% of de novo AML patients harboring CEBPα mutations at diagnosis retained the original clones at relapse. CEBPα mutations did not involve in the pathogenesis of chronic myeloid leukemia with AML transformation, while emergence of clones carrying CEBPα mutations was observed in a subset of patients in the progression of MDS to AML.

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