Project 1 - Molecular Determinants of Decitabine Responses.

项目摘要 该项目的长期目标是确定哪些急性髓系白血病(AML)患者是 最有可能对地西他滨治疗有反应，并确定其分子机制 地西他滨反应。我们最近报道了TP53突变的AML和MDS患者，这两种患者具有很高的 复发的风险和非常糟糕的结果，对地西他滨的反应始终如一，地西他滨是一种低甲基化药物，可以 作为门诊病人服用，这在大多数患者中耐受性很好。然而，大多数有反应的患者都这样做了 没有TP53突变，这表明其他途径也可以影响地西他滨的敏感性。这个 与地西他滨反应和随后复发相关的分子机制目前尚不清楚。 为了完善和扩展这些调查结果，我们提出了以下具体目标： 目的1.我们将确定地西他滨抢救治疗急性髓系白血病合并TP53的疗效。 突变。复发/难治的AML患者和携带TP53突变的患者具有超高风险 结果极差的人群，代表着未得到满足的治疗需求。因此，我们将治疗60 已知在28天周期的第1-10天使用地西他滨的复发/难治性AML患者具有TP53突变 在3个中心(华盛顿大学、弗雷德·哈钦森癌症研究中心和爱荷华大学)。 如果可能，有反应的患者将接受同种异体移植以进行巩固治疗。我们会 确定1年的总存活率，以及应答率、移植时间、白血病复发时间、 以及周期1和周期2的平均住院天数。 目的2.我们将定义与地他滨反应相关的基因组和表观基因组特征。 我们将使用增强的全基因组测序来确定TP53野生型患者是否患有 复发、非基因突变，以及复发时是否获得复发突变，与TP53无关 状态。我们将把全基因组亚硫酸氢盐测序与RNA-Seq相结合来确定地西他滨 导致特定的和规范的DNA低甲基化模式，这些变化是否导致一致 转录特征，以及这些模式中是否有任何与临床结果相关。

Project Summary The long-term goal of this project is to identify the patients with acute myeloid leukemia (AML) who are the most likely to respond to decitabine therapy, and to determine the molecular mechanisms of decitabine responses. We recently reported that TP53 mutated AML and MDS patients, which have a high risk of relapse, and very poor outcomes, respond consistently to decitabine, a hypomethylating agent that can be given as an outpatient, and which is well tolerated in most patients. However, most responding patients did not have TP53 mutations, suggesting that other pathways can also influence decitabine sensitivity. The molecular mechanisms associated with decitabine responses and subsequent relapse are currently unclear. To refine and extend these findings, we propose the following specific aims: Aim 1. We will determine the efficacy of decitabine salvage therapy in AML patients with TP53 mutations. Patients with relapsed/refractory AML and with TP53 mutations represent an ultra-high-risk population with extremely poor outcomes, representing an unmet therapeutic need. We will therefore treat 60 relapsed/refractory AML patients known to have TP53 mutations with decitabine on days 1-10 of 28-day cycles at 3 centers (Washington University, Fred Hutchinson Cancer Research Center, and the University of Iowa). Responding patients will undergo allogeneic transplantation for consolidation therapy, if possible. We will determine the overall survival at 1 year, as well as response rates, time to transplant, time to leukemia relapse, and the average number of hospital days during cycles 1 and 2. Aim 2. We will define the genomic and epigenomic signatures associated with decitabine responses. We will use enhanced whole genome sequencing to determine whether TP53 wild-type patients have recurrent, non-genic mutations, and whether recurrent mutations are acquired at relapse, regardless of TP53 status. We will integrate whole genome bisulfite sequencing with RNA-Seq to determine whether decitabine causes specific and canonical patterns of DNA hypomethylation, whether these changes result in consistent transcriptional signatures, and whether any of these patterns correlate with clinical outcomes.