ARUP Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, UT, USA.
Leuk Res. 2011 Feb;35(2):200-7. doi: 10.1016/j.leukres.2010.09.018. Epub 2010 Oct 20.
Loss of function mutations in CCAAT/enhancer binding protein alpha (CEBPA) have been identified in acute myeloid leukemia (AML) and bi-allelic (double) CEBPA mutations are associated with improved prognosis in cases of cytogenetically normal-AML. In a subset of AML patients lacking CEBPA mutations, core promotor methylation of CEBPA has been described and is associated with a gene expression profile similar to the mutated cases including the expression of T cell associated genes such as CD7. However, the overall incidence and pattern of CEBPA mutations and core promoter methylation has not been thoroughly explored in a larger subset of AML with expression of CD7. Here we describe a simple and clinically deployable CEBPA promoter methylation test and the results of combined testing for CEBPA mutations and promoter methylation in 102 cases of AML, including 43 CD7+ cases. Overall, there were 5 methylated cases, 6 cases with double mutations, and 3 cases with single mutations. Significantly, 10 of 43 CD7+ cases (23%) had either methylated or double-mutated CEBPA. The CD7+ subset included all 5 methylated cases and 5 of the 6 cases with double mutations. All 3 cases with single mutations were CD7-. No case exhibited both hypermethylation and mutations. We find that promoter methylation accounts for half of those CD7+ cases with CEBPA dysregulating abnormalities. Furthermore, methylated cases and those with bi-allelic CEBPA mutations have similar phenotypic features including expression of CD7 and lack of co-incident NPM1 mutations. Our study suggests that methylation testing may be as important as mutation testing for identifying AML cases with CEBPA dysregulation and may be indicated in the routine prognostic workup of AML.
CEBPA（CCAAT/增强子结合蛋白α）功能缺失突变已在急性髓系白血病（AML）中被发现，双等位基因（双重）CEBPA 突变与核型正常的 AML 病例的预后改善相关。在缺乏 CEBPA 突变的 AML 患者亚组中，已描述了 CEBPA 核心启动子甲基化，并且与突变病例的基因表达谱相似，包括 T 细胞相关基因如 CD7 的表达。然而，在具有 CD7 表达的更大 AML 患者亚组中，尚未彻底探讨 CEBPA 突变和核心启动子甲基化的总体发生率和模式。在这里，我们描述了一种简单且可在临床上部署的 CEBPA 启动子甲基化检测方法，以及在包括 43 例 CD7+病例在内的 102 例 AML 病例中进行 CEBPA 突变和启动子甲基化联合检测的结果。总体而言，有 5 例甲基化病例，6 例双突变病例和 3 例单突变病例。显著的是，43 例 CD7+病例中有 10 例（23%）存在 CEBPA 甲基化或双突变。CD7+亚组包括所有 5 例甲基化病例和 6 例双突变病例中的 5 例。所有 3 例单突变病例均为 CD7-。没有病例同时表现出高度甲基化和突变。我们发现，启动子甲基化占 CD7+病例中 CEBPA 调节异常的一半。此外，甲基化病例和具有双等位基因 CEBPA 突变的病例具有相似的表型特征，包括 CD7 的表达和缺乏同时发生的 NPM1 突变。我们的研究表明，甲基化检测可能与突变检测一样重要，用于确定 CEBPA 失调的 AML 病例，并且可能在 AML 的常规预后评估中具有指示作用。
