Laboratory for Leukemia Diagnostics, Department of Internal Medicine III, University of Munich-Grosshadern, München, Germany.
J Clin Oncol. 2010 Feb 1;28(4):570-7. doi: 10.1200/JCO.2008.21.6010. Epub 2009 Dec 28.
CEBPA mutations are found as either biallelic (biCEBPA) or monoallelic (moCEBPA). We set out to explore whether the kind of CEBPA mutation is of prognostic relevance in cytogenetically normal (CN) acute myeloid leukemia (AML).
Four hundred sixty-seven homogeneously treated patients with CN-AML were subdivided into moCEBPA, biCEBPA, and wild-type (wt) CEBPA patients. The subgroups were analyzed for clinical parameters and for additional mutations in the NPM1, FLT3, and MLL genes. Furthermore, we obtained gene expression profiles using oligonucleotide microarrays.
Only patients with biCEBPA had an improved median overall survival when compared with patients with wtCEBPA (not reached v 20.4 months, respectively; P = .018), whereas patients with moCEBPA (20.9 months) and wtCEBPA had a similar outcome (P = .506). Multivariable analysis confirmed biCEBPA, but not moCEBPA, mutations as an independent favorable prognostic factor. Interestingly, biCEBPA mutations, compared with wtCEBPA, were never associated with mutated NPM1 (0% v 43%, respectively; P < .001) and rarely associated with FLT3 internal tandem duplication (ITD; 5% v 23%, respectively; P = .059), whereas patients with moCEBPA had a similar frequency of mutated NPM1 and a significantly higher association with FLT3-ITD compared with patients with wtCEBPA (44% v 23%, respectively; P = .037). Furthermore, patients with biCEBPA showed a homogeneous gene expression profile that was characterized by downregulation of HOX genes, whereas patients with moCEBPA showed greater heterogeneity in their gene expression profiles.
Biallelic disruption of the N and C terminus of CEBPA is required for the favorable clinical outcome of CEBPA-mutated patients and represents a distinct molecular subtype of CN-AML with a different frequency of associated gene mutations. These findings are of great significance for risk-adapted therapeutic strategies in AML.
CEBPA 突变要么为双等位基因（biCEBPA）突变，要么为单等位基因（moCEBPA）突变。本研究旨在探讨在细胞遗传学正常（CN）急性髓系白血病（AML）中，CEBPA 突变的类型是否与预后相关。
将 467 例同质治疗的 CN-AML 患者分为 moCEBPA、biCEBPA 和野生型（wt）CEBPA 患者。分析这些亚组的临床参数以及 NPM1、FLT3 和 MLL 基因的其他突变。此外，我们还使用寡核苷酸微阵列获得了基因表达谱。
与 wtCEBPA 相比，仅 biCEBPA 患者的中位总生存期得到改善（未达到 v 20.4 个月，P =.018），而 moCEBPA（20.9 个月）和 wtCEBPA 患者的结局相似（P =.506）。多变量分析证实，biCEBPA 突变而非 moCEBPA 突变是独立的有利预后因素。有趣的是，与 wtCEBPA 相比，biCEBPA 突变从未与突变型 NPM1 相关（分别为 0% v 43%，P <.001），与 FLT3 内部串联重复（ITD）相关的频率也较低（分别为 5% v 23%，P =.059），而 moCEBPA 患者的突变型 NPM1 频率相似，与 wtCEBPA 患者相比，FLT3-ITD 的相关性显著更高（分别为 44% v 23%，P =.037）。此外，biCEBPA 患者表现出同质的基因表达谱，其特征是 HOX 基因下调，而 moCEBPA 患者的基因表达谱则表现出更大的异质性。
CEBPA 的 N 端和 C 端双等位基因缺失是 CEBPA 突变患者临床结局良好的必要条件，代表了 CN-AML 的一个独特分子亚型，与相关基因突变的频率不同。这些发现对 AML 的风险适应治疗策略具有重要意义。
