Genome-wide gene expression in CEBPA mutant and CEBPA silenced AML and in T-ALL. Homo sapiens

Acute Myeloid Leukemia (AML) is a heterogeneous disease from the molecular and biological standpoints, and even patients with a specific gene expression profile may present clinical and molecular heterogeneity. We studied the epigenetic profiles of a cohort of patients that shared a common gene expression profile but differed in that only half of them harbored mutations of the CEBPA locus, while the rest presented with silencing of this gene and co-expression of certain T cell markers. DNA methylation studies revealed that these two groups of patients could be readily segregated in an unsupervised fashion based on their DNA methylation profiles alone. Furthermore, CEBPA silencing was associated with the presence of an aberrant DNA hypermethylation signature, which was not present in the CEBPA mutant group. This aberrant hypermethylation occurred more frequently at sites within CpG islands. CEBPA silenced leukemias also displayed marked hypermethylation when compared with normal CD34+ hematopoietic cells, while CEBPA mutant cases showed only mild changes in DNA methylation when compared to these normal progenitors. Biologically, CEBPA silenced leukemias presented with a decreased response to myeloid growth factors in vitro. Keywords: Gene expression profiling using arrays Overall design: Direct comparison of gene expression in leukemic blasts from 8 patients with Acute Myeloid Leukemia (AML) carrying a CEBPA mutation and 8 patients with AML without CEBPA mutation but with silencing of CEBPA expression, and with 9 samples of T Acute Lymphoblastic Leukemia (T-ALL) patients.

急性髓系白血病（Acute Myeloid Leukemia, AML）是一类从分子与生物学层面具有异质性的疾病，即便携带特定基因表达谱的患者，也可表现出临床与分子层面的异质性。本研究针对一组具有共同基因表达谱的患者队列展开表观遗传谱分析，该队列的差异在于：仅半数患者携带CEBPA位点突变，其余患者则表现为该基因沉默，并伴随特定T细胞标志物的共表达。DNA甲基化研究显示，仅凭借自身的DNA甲基化谱，即可通过无监督聚类方式轻易区分这两组患者。此外，CEBPA基因沉默与异常DNA高甲基化特征相关，而该特征并未出现在CEBPA突变组中。此类异常高甲基化事件更频繁地发生于CpG岛区域内。与正常CD34+造血干细胞相比，CEBPA沉默型白血病同样呈现显著的甲基化升高；而CEBPA突变型病例相较于上述正常造血祖细胞，仅表现出轻微的DNA甲基化变化。在生物学层面，CEBPA沉默型白血病在体外对髓系生长因子的反应性有所降低。关键词：基于芯片的基因表达谱分析 整体实验设计：直接对比8例携带CEBPA突变的急性髓系白血病患者的白血病母细胞、8例无CEBPA突变但存在CEBPA基因沉默且伴随特定T细胞标志物共表达的急性髓系白血病患者的白血病母细胞，以及9例T细胞急性淋巴细胞白血病（T Acute Lymphoblastic Leukemia, T-ALL）患者的样本。