Gene expression profiling of 35 AML FAB-M0 samples. Homo sapiens

Ficolled AML-M0 sample gene expression profiles on Affymetrix HGU133Plus2.0 GeneChips. Acute myeloid leukemia (AML) classified as FAB-M0 is defined as a subtype with minimally differentiated morphology. Here we investigated by gene expression (GEP) profiling whether AML-M0 cases should be considered as one or more unique molecular subgroups that discriminates them from other AML patients. By applying GEP and subsequent unsupervised analysis of 35 AML-M0 samples and 253 previously reported AML cases, we demonstrate that AML-M0 cases express a unique signature. Hematological transcription regulators such as CEBPA, CEBPD, PU.1 and ETV6 and the differentiation associated gene MPO appeared strongly down-regulated, in line with the very primitive state of this type of leukemia. Moreover, AML M0 cases appeared to have a strong positive correlation with a previously defined immature AML subgroup with adverse prognosis. AML-M0 leukemias frequently carry loss-of-function RUNX-1 mutation and unsupervised analyses revealed a striking distinction between cases with and without mutations. RUNX1 mutant AML-M0 samples showed a distinct up-regulation of B-cell-related genes, e.g. members of the B-cell receptor complex, transcriptions regulators RUNX3, ETS2, IRF8 or PRDM1 and major histocompatibility complex class II genes. Importantly, expression of one single gene, i.e. BLNK, enabled prediction of RUNX1 mutations in AML-M0 with high accuracy. We propose that RUNX1 mutations in this subgroup of AML cause lineage infidelity, leading to aberrant co-expression of myeloid and B-lymphoid genes in the same cells. Overall design: 35 samples

采用Affymetrix HGU133Plus2.0基因芯片检测的经聚蔗糖（Ficoll）分离处理的AML-M0样本基因表达谱。急性髓系白血病（AML）的FAB-M0亚型，被定义为形态学分化程度极低的白血病亚型。本研究通过基因表达谱（GEP, Gene Expression Profiling）分析，探究AML-M0病例是否应被划分为一个或多个独特的分子亚型，以区分其与其他AML患者。本研究对35例AML-M0样本与253例已发表的AML病例开展基因表达谱分析及后续无监督分析（unsupervised analysis），结果显示AML-M0病例具有独特的分子特征。造血系统转录调控因子（如CEBPA、CEBPD、PU.1、ETV6）以及分化相关基因MPO均呈现显著下调，这与该类白血病的原始未分化状态相符。此外，AML-M0病例与此前定义的预后不良的未成熟AML亚型呈现显著正相关。AML-M0白血病常携带功能丧失型RUNX1突变，无监督分析结果显示，携带与未携带该突变的病例之间存在显著差异。携带RUNX1突变的AML-M0样本中，B细胞相关基因（如B细胞受体复合物成员、转录调控因子RUNX3、ETS2、IRF8、PRDM1以及主要组织相容性复合体（MHC）II类基因）呈现显著上调。值得注意的是，仅通过单个基因BLNK的表达水平，即可高精度预测AML-M0病例的RUNX1突变状态。本研究提出，该AML亚型中的RUNX1突变会导致细胞谱系保真度缺失，进而使髓系与B淋巴细胞系基因在同一细胞中出现异常共表达。实验整体设计：共纳入35例AML-M0样本