The emergence of a C/EBPα mutation in the clonal evolution of MDS towards secondary AML
The emergence of a C/EBPα mutation in the clonal evolution of MDS towards secondary AML
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DOI：
10.1038/sj.leu.2402805
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发表时间：
2003-02-01
期刊：
影响因子：
11.4
通讯作者：
Verbeek, W
中科院分区：
文献类型：
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作者：
Kaeferstein, A;Krug, U;Verbeek, W
最近，在急性髓系白血病 (AML) 中发现了转录因子 CCAAT/增强子结合蛋白 α (C/EBPα) 的突变。我们对骨髓增生异常综合征和伴有 MDS 的 AML 中的 C/EBPα 基因进行了突变分析。在难治性贫血 (0/27)、环状铁粒幼细胞难治性贫血 (0/7)、原始细胞过多难治性贫血 (RAEB 0/16) 或慢性粒单核细胞白血病 (CMML 0/5) 患者中未发现突变。继发于 MDS 的 RAEB-T/AML 患者中，每 13 名患者中就有 1 名显示出 C/EBPα 基因突变。在该患者中，一个 4 bp 的插入破坏了一个等位基因中的密码子 69。新颖的是+1移码预计会产生107个氨基酸的截短蛋白质。然而，翻译的主要蛋白质是C/EBPα同种型p30，其先前被证明可以抑制C/EBPαp42的DNA结合和反式激活特性。有趣的是，在最初的 RAEB 和 RAEB-T 阶段诊断时无法检测到这种突变。该突变出现在 RAEB-T 化疗后复发时。我们得出的结论是，C/EBPα 突变对于初始爆炸积累并不是必需的。复发时携带 C/EBPα 突变的韧皮克隆的出现表明，这种突变可能赋予已形成分化障碍的骨髓细胞生长优势。
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/EBPa gene. In this patient a 4 bp insertion disrupted codon 69 in one allele. Is novel +1 frame shift is predicted to result in a truncated protein of 107 amino acids. However, the dominant protein translated was the C/EBPa 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.