The emergence of a C/EBPalpha mutation in the clonal evolution of MDS towards secondary AML.
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.
Kaeferstein
A
A
Division of Hematology-Oncology, Medizinische Hochschule Hannover, Germany.
Krug
U
U
Tiesmeier
J
J
Aivado
M
M
Faulhaber
M
M
Stadler
M
M
Krauter
J
J
Germing
U
U
Hofmann
W K
WK
Koeffler
H P
HP
Ganser
A
A
Verbeek
W
W
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
D022763:CCAAT-Enhancer-Binding Protein-alpha; D017931:DNA Primers