Integrated transcript and genome analyses reveal NKX2-1 and MEF2C as potential oncogenes in T-ALL. Homo sapiens

To identify novel oncogenic pathways in T-cell acute lymphoblastic leukemia (T-ALL), we combined expression profiling of 117 pediatric patient samples and detailed molecular cytogenetic analyses including the Chromosome Conformation Capture on Chip (4C) method. Two T-ALL subtypes were identified that lacked rearrangements of known oncogenes. One subtype associated with cortical arrest, expression of cell cycle genes and ectopic NKX2-1 or NKX2-2 expression for which rearrangements were identified. The second subtype associated with immature T-cell development and high expression of the MEF2C transcription factor as consequence of rearrangements of MEF2C, transcription factors that target MEF2C or MEF2C-associated cofactors. We propose NKX2-1, NKX2-2 and MEF2C as T-ALL oncogenes that are activated by various rearrangements. Overall design: This study includes 117 pediatric T-ALL samples of which 92 samples are available at GSE10609. In addition, this study includes 7 normal bone marrow control samples

为鉴定T细胞急性淋巴细胞白血病（T-cell acute lymphoblastic leukemia, T-ALL）中新的致癌通路，我们整合了117例儿科患者样本的表达谱分析，以及包含染色体构象捕获芯片（Chromosome Conformation Capture on Chip, 4C）技术在内的精细分子细胞遗传学分析。本研究鉴定出两类未携带已知致癌基因重排的T-ALL亚型：其中一类亚型与T细胞皮质发育阻滞、细胞周期基因表达上调以及NKX2-1或NKX2-2异位表达相关，且已在该类亚型中检测到对应基因重排事件；另一类亚型则与未成熟T细胞发育状态相关，其MEF2C转录因子高表达源于MEF2C基因、靶向MEF2C的转录因子或MEF2C相关辅因子发生的基因重排。我们提出将NKX2-1、NKX2-2及MEF2C视为可通过多种重排机制激活的T-ALL致癌基因。整体实验设计：本研究纳入117例儿科T-ALL样本，其中92例样本可于GSE10609数据集获取。此外，本研究同时纳入7例正常骨髓对照样本。