Integrative Epigenomic Analysis Identifies Biomarkers and Therapeutic Targets in Adult B-Acute Lymphoblastic Leukemia [mRNA profiling]. Homo sapiens

We performed DNA methylation (HELP array) and gene expression profiling in 215 samples of adult B-lineage acute lymphoblastic leukemia (ALL) and 12 normal preB samples. Adult B-lineage acute lymphoblastic leukemia (B-ALL) is an aggressive disease with <40% long-term survival. Genetic alterations such as BCR/ABL, E2A/PBX1 and MLL rearrangement (tMLL) define distinct B-ALL subtypes, which are associated with poor clinical outcome. It has been shown that these B-ALL subtypes have distinct expression profiles. However, the role of the epigenome in shaping these expression profiles and how the aberrant epigenetic gene regulation contributes to the biological and clinical features of those ALL subtypes is largely unknown. To address this question, we performed genome-wide DNA methylation and gene expression profiling on a large cohort of 215 well-characterized adult B-ALL specimens from the ECOG E2993 phase III clinical trial and a cohort of normal precursor B (preB) cells from 12 healthy bone marrows. The integrative analysis of these profiles led to the identification of key gene networks deregulated at the epigenetic and transcriptional levels within each subtype. In BCR/ABL, we identified a network centered on IL2RA(CD25), which is itself hypomethylated and overexpressed in most BCR/ABL B-ALL and confers poor clinical outcomes. In the tMLL subtype, we uncovered aberrant epigenetic and transcriptional activities that include hypomethylation and upregulation of FLT3 and BCL6. After showing that MLL/AF4 fusion protein binds to these genes as well as other hypomethylated and overexpressed genes in tMLL ALL cells, we showed that a specific BCL6 inhibitor, RI-BPI, kills tumor cells in both tMLL ALL cell lines and patient samples. BCL6 inhibition may therefore represent a novel therapeutic strategy for B-ALL patients with MLL translocations. Overall design: Expression profiling in 191 samples of adult B-lineage acute lymphoblastic leukemia (ALL) and 3 normal preB samples This submission represents transcriptome component of study.

我们对215例成人B系急性淋巴细胞白血病（B-lineage acute lymphoblastic leukemia, B-ALL）样本及12例正常前B（preB）细胞样本，开展了DNA甲基化（HELP array）检测与基因表达谱分析。成人B系急性淋巴细胞白血病是一种侵袭性恶性疾病，长期存活率不足40%。诸如BCR/ABL、E2A/PBX1及MLL重排（tMLL）等遗传变异，可界定出不同的B-ALL亚型，此类亚型均与不良临床结局相关。已有研究证实，这些B-ALL亚型具有独特的表达谱，但表观基因组在塑造此类表达谱中所发挥的作用，以及异常表观遗传基因调控如何影响此类ALL亚型的生物学与临床特征，目前仍未得到充分阐明。为解答上述科学问题，我们对来自ECOG E2993Ⅲ期临床试验的215例经过充分表征的成人B-ALL队列标本，以及来自12名健康个体骨髓的正常前B细胞队列，开展了全基因组DNA甲基化与基因表达谱分析。对上述两组组学数据的整合分析，成功鉴定出各亚型中表观遗传与转录水平失调的关键基因调控网络。在BCR/ABL亚型中，我们鉴定出以IL2RA（CD25）为核心的基因调控网络：该基因在大多数BCR/ABL型B-ALL中呈低甲基化与过表达状态，且与不良临床结局密切相关。在tMLL亚型中，我们发现了异常的表观遗传与转录调控活动，包括FLT3与BCL6的低甲基化及上调。我们证实，MLL/AF4融合蛋白可结合此类基因，以及tMLL型ALL细胞中其他低甲基化且过表达的基因；进一步实验表明，特异性BCL6抑制剂RI-BPI可杀伤tMLL型ALL细胞系及患者样本中的肿瘤细胞。因此，BCL6抑制或许可作为携带MLL易位的B-ALL患者的新型治疗策略。整体实验设计：本研究的表达谱分析涉及191例成人B系急性淋巴细胞白血病样本及3例正常前B细胞样本，本次提交为该研究的转录组组成部分。