Combined epigenetic therapy of acute myeloid leukemia: translational studies of in vivo induction of gene expression and DNA hypomethylation

急性髓性白血病的联合表观遗传学治疗：体内诱导基因表达和 DNA 低甲基化的转化研究

• 批准号: 172102549
• 负责人: Professor Dr. Michael Lübbert, Ph.D.
• 金额: --
• 依托单位: Klinik für Innere Medizin I - Hämatologie, Onkologie und Stammzelltransplantation
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/172102549?language=en
• 关键词: Combined; epigenetic; therapy; acute; myeloid

DNA hypomethylating azanucleoside drugs provide active, non-intensive treatment of older AML/MDS patients, but the mechanisms governing their in vivo activity is as yet not fully understood. Using primary myeloid blasts from patients treated within the 4-arm randomized phase II "DECIDER" AML trial with 5-aza-2'-deoxycytidine (5-aza-dC, Decitabine, DAC) with or without the histone deacety-lase (HDAC) inhibitor valproic acid (VPA) and all-trans retinoic acid (ATRA, a differentiation-inducing agent active in acute promyelocytic leukemia), in Specific Aim 1 we will ask whether the epigenetic treatment induces distinct, early DNA methylation changes in the leukemic blasts only or also in normal, "bystander" T-cells and, in selected patients, in normal CD34+ hematopoietic precursors. Also we will address differential changes induced by Decitabine and 5-azacytidine in vivo, and whether de- and re-methylation is a random or non-random process in the primary cells studied. Specific Aim 2 focusses on the question: which treatment-induced DNA methylation changes correlate with mRNA expression changes? Here we also hope to generate a "response signature" to predict hematologic response by genes consistently derepressed/demethylated in the patients. In Specific Aim 3 we shall address which genes encoding Cancer/testis antigens are induced, and whether this is associated with demethylation of the genes. We hope that the generated methylome and transcriptome profiles of the cells from the epi-genetically treated leukemia patients will enable us to identify genome-wide targets of this treatment ap-proach, the extent of Decitabine DNA demethylating activity in malignant vs. normal blood cells, and hopefully a signature of clinical response to the epigenetic therapy. The long-term research goal is a bet-ter understanding of the mechanisms of action of epigenetically active agents in vivo, including those not directly linked to DNA hypomethylation.

DNA低甲基化氮杂核苷药物为老年AML/MDS患者提供了积极的非强化治疗，但其体内活性的机制尚未完全了解。使用在4组随机II期“DECIDER”AML试验中接受5-氮杂-2 '-脱氧胞苷治疗的患者的原代髓系原始细胞（5-aza-dC、地西他滨、DAC），伴或不伴组蛋白脱乙酰酶（HDAC）抑制剂丙戊酸（VPA）和全反式维甲酸（ATRA，一种在急性早幼粒细胞白血病中有活性的分化诱导剂），在具体目标1中，我们将询问表观遗传治疗是否诱导不同的，仅在白血病原始细胞中，或在正常的“旁观者”T细胞中，以及在选定的患者中，在正常的CD 34+造血前体细胞中，早期DNA甲基化改变。此外，我们还将讨论地西他滨和5-氮杂胞苷在体内诱导的差异变化，以及在所研究的原代细胞中去甲基化和再甲基化是否是随机或非随机过程。具体目标2关注的问题是：哪些处理诱导的DNA甲基化变化与mRNA表达变化相关？在这里，我们也希望产生一个“响应签名”，以预测血液反应的基因一致去抑制/去甲基化的患者。在具体目标3中，我们将讨论哪些编码癌症/睾丸抗原的基因被诱导，以及这是否与基因的去甲基化有关。我们希望，所产生的表观遗传治疗的白血病患者的细胞的甲基化组和转录组谱将使我们能够鉴定该治疗方法的全基因组靶点，恶性与正常血细胞中地西他滨DNA去甲基化活性的程度，并希望鉴定对表观遗传治疗的临床应答的特征。长期的研究目标是更好地理解表观遗传活性剂在体内的作用机制，包括那些与DNA低甲基化没有直接联系的作用机制。