title: The emergence of a C/EBPalpha mutation in the clonal evolution of MDS towards secondary AML.
abstract: Recently, mutations in the transcription factor CCAAT/ enhancer binding protein alpha (C/EBPalpha) have been described in acute myeloid leukemia (AML). We performed a mutational analysis of the C/EBPalpha gene in the myelodysplastic syndromes and AML with antecedent MDS. No mutations were found in patients with refractory anemia (0/27), refractory anemia with ringed sideroblasts (0/7), refractory anemia with excess of blasts (RAEB 0/16) or chronic myelomonocytic leukemia (CMML 0/5). One out of 13 patients with RAEB-T/AML secondary to MDS showed a mutation in the C/EBPalpha gene. In this patient a 4 bp insertion disrupted codon 69 in one allele. This novel +1 frame shift is predicted to result in a truncated protein of 107 amino acids. However, the dominant protein translated was the C/EBPalpha isoform p30, which was previously shown to inhibit the DNA-binding and transactivation properties of C/EBPalpha p42. Interestingly this mutation could not be detected at diagnosis in the initial RAEB and RAEB-T stage. The mutation appeared at relapse after chemotherapy for RAEB-T. We conclude that the C/EBPalpha mutation was not essential for the initial blast accumulation. The emergence of a bast clone carrying a C/EBPalpha mutation at relapse indicates that this mutation may confer a growth advantage in a myeloid cell with an established differentiation block.
authors.affiliation: Division of Hematology-Oncology, Medizinische Hochschule Hannover, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Kaeferstein
authors.forename: U
authors.initials: U
authors.lastname: Krug
authors.forename: J
authors.initials: J
authors.lastname: Tiesmeier
authors.forename: M
authors.initials: M
authors.lastname: Aivado
authors.forename: M
authors.initials: M
authors.lastname: Faulhaber
authors.forename: M
authors.initials: M
authors.lastname: Stadler
authors.forename: J
authors.initials: J
authors.lastname: Krauter
authors.forename: U
authors.initials: U
authors.lastname: Germing
authors.forename: W K
authors.initials: WK
authors.lastname: Hofmann
authors.forename: H P
authors.initials: HP
authors.lastname: Koeffler
authors.forename: A
authors.initials: A
authors.lastname: Ganser
authors.forename: W
authors.initials: W
authors.lastname: Verbeek
mesh_terms: D000328:Adult; D000368:Aged; D000754:Anemia, Refractory, with Excess of Blasts / Q000235:genetics / Q000473:pathology; D001483:Base Sequence; D001854:Bone Marrow Cells / Q000473:pathology*; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism*; D017931:DNA Primers; D018450:Disease Progression; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000150:complications / Q000235:genetics* / Q000473:pathology; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D017931:DNA Primers