Favorable prognostic significance of CEBPA mutations in patients with de novo acute myeloid leukemia:: a study from the Acute Leukemia French Association (ALFA)
Favorable prognostic significance of CEBPA mutations in patients with de novo acute myeloid leukemia:: a study from the Acute Leukemia French Association (ALFA)
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DOI：
10.1182/blood-2002-03-0990
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发表时间：
2002-10-15
期刊：
影响因子：
20.3
通讯作者：
Dombret, H
中科院分区：
文献类型：
--
作者：
Preudhomme, C;Sagot, C;Dombret, H
转录因子C/EBPalpha对于成熟粒细胞的分化至关重要。最近，在近10%的急性髓性白血病（AML）患者中描述了可能诱导分化停滞的不同CEBPA基因突变。在本研究中，我们回顾性分析了CEBPA突变在135例AML患者中的预后意义（排除法-美-英[FAB]-M3）。所有患者均于1990年至1996年前瞻性入选ALFA（急性白血病法国协会）组的多中心试验（中位年龄45岁，中位随访时间5.7年）。使用CEBPA基因的直接测序来评估突变。在135名受试者中，有15名（11%）发现了22种突变。12名患者至少有一个位于蛋白质N-末端部分的突变，导致全长C/EBPalpha蛋白表达缺失。CEBPA突变仅存在于属于中等细胞遗传学风险亚组的患者中，并与FAB-M1亚型相关（P = 0.02）。FLT 3内部串联重复（ITD）被发现在5的15 CEBPA突变相比，30的119 CEBPA非突变的情况下测试（P = 0.54）。CEBPA突变的存在被认为是一个独立的预后良好的因素，即使在调整细胞遗传学和FLT 3状态后（估计5年总生存率为53%对25%，P = 0.04）。FLT 3-ITD似乎是CEBPA突变AML患者的主要不良预后因素。因此，我们提出了一个风险分类，包括在有利的亚组中的所有患者的中间亚组显示CEBPA突变时，不与FLT 3-ITD。
The transcription factor C/EBPalpha is crucial for differentiation of mature granulocytes. Recently, different CEBPA gene mutations likely to induce differentiation arrest have been described in nearly 10% of patients with acute myeloid leukemia (AML). In the present study, we retrospectively analyzed the prognostic significance of CEBPA mutations in 135 AML patients (French-American-British [FAB]-M3 excluded). All patients were prospectively enrolled between 1990 and 1996 in a multicenter trial of the ALFA (Acute Leukemia French Association) Group (median age 45 years, median follow-up 5.7 years). Mutations Were assessed using direct sequencing of the CEBPA gene. Twenty-two mutations were found in 15 (11%) of 135 patients tested. Twelve patients had at least one mutation located in the N-terminal part of the protein leading to the lack of expression of the full-length C/EBPalpha protein. CEBPA mutations were present only in patients belonging to the intermediate cytogenetic risk subgroup and associated with the FAB-M1 subtype (P = .02). FLT3 internal tandem duplication (ITD) was found in 5 of 15 CEBPA-mutated as compared with 30 of 119 CEBPA-nonmutated cases tested (P = .54). Presence of CEBPA mutations was identified as an independent good prognosis factor for outcome even after adjustment on cytogenetics and FLT3 status (estimated 5-year overall survival 53% vs 25%, P = .04). FLT3-ITD appeared to act as a major bad prognosis factor in patients with CEBPA-mutated AML. We thus propose a risk classification that includes in the favorable subgroup all patients from the intermediate subgroup displaying CEBPA mutations when not associated with FLT3-ITD.