Understanding and Targeting Chemotherapy Resistance in Acute Myeloid Leukemia

了解和针对急性髓系白血病的化疗耐药性

• 批准号: 9114538
• 负责人: MARTIN CARROLL
• 金额: $ 66.31万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-22 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9114538
• 关键词: Acute Myelocytic Leukemia; Address; Affect; Aftercare; Anthracyclines; Ara-C; Azacitidine; BCL6 gene; Cells; Chemosensitization; Clinical; Complex; Cytarabine; Cytosine; DNA Methylation; DNA Methyltransferase Inhibitor; Data; Diagnosis; Disease; Down-Regulation; EZH2 gene; Elements; Enzymes; Epigenetic Process; Event; Exons; Gene Targeting; Genes; Genetic; Genetic Determinism; HDAC9 gene; Health; Hematopoietic Neoplasms; Histone-Lysine N-Methyltransferase; Histones; Human; In Vitro; Lead; Lesion; Leukemic Cell; Methylation; Modeling; Molecular; Molecular Abnormality; Mus; Mutation; Pathway interactions; Patients; Phenotype; Population; Property; Regulation; Relapse; Resistance; Role; Sampling; Specimen; Stress; Study models; Testing; Time; Up-Regulation; Xenograft procedure; chemotherapy; cohort; genetic signature; histone methylation; in vivo; inhibitor/antagonist; leukemia; leukemic stem cell; mortality; novel; response; transcription factor; transcriptome sequencing

 DESCRIPTION (provided by applicant): Chemotherapy resistance is the most important clinical challenge in treating patients with acute myeloid leukemia (AML). The majority of patients with AML initially respond to chemotherapy but over half of responders will relapse and eventually die of disease. Traditionally, chemotherapy resistance is hypothesized to represent selection for a genetically distinct clone that has properties of leukemic stem cells (LSC). Recent data and our preliminary results (below) indicate that neither part of this model is fully correct. Rather, we propose that chemotherapy resistance can and frequently is an acquired epigenetic response to chemotherapeutic challenge that may arise in any leukemic clone. In vitro, we have modeled chemotherapy resistance and demonstrate that both DNA methylation and histone methylation are altered rapidly (within days) after treatment with Ara-C. Specifically, H3K27me3 is increased and H3K4me2 is decreased. In order to initially study the contribution of epigenetic changes in primary cells, we have compared the genetic and DNA methylation signature of 140 pairs of AML cells at diagnosis and relapse. Importantly, preliminary evidence suggests that at least 20% of patients have no new detectable genetic abnormalities at relapse. In contrast, when comparing paired diagnosis vs. relapse AML specimens we observe extensive and partially convergent redistribution of cytosine methylation affecting specific pathways, regardless of genetic background. Taken together these studies suggest an epigenetic mechanism of chemotherapy resistance but do not address the role of leukemic stem cells. To address this, we have studied the effect of cytosine arabinoside (Ara-C) on AML cells xenografted in NSG mice. Importantly, we demonstrate for the first time that limiting dilution analysis of Ara-C treatd AML cells does NOT show an enrichment in SCID-leukemia initiating cells. Collectively these data lead us to hypothesize that chemotherapy resistance in AML is a biologically complex event that includes but is not fully explained by genetic lesions and is composed of both fixed and inducible epigenetic elements. To test and explore these ideas, we propose 3 Specific Aims: Specific Aim 1) Identify and characterize candidate mechanisms of epigenetic response to Ara-C in AML cells in vitro. Specific Aim 2) Identify epigenetic and genetic determinants of relapse in primary AML patient samples. Specific Aim 3) Determine the dynamics and mechanism through which chemoresistant features emerge in leukemic cell populations.

 描述（由申请人提供）：化疗耐药是治疗急性髓系白血病 (AML) 患者最重要的临床挑战。大多数 AML 患者最初对化疗有反应，但传统上超过一半的反应者会复发并最终死于疾病。 ，化疗耐药性被捕获来代表对具有白血病干细胞（LSC）特性的遗传上不同的克隆的选择。 数据和我们的初步结果（如下）表明该模型的任何一部分都不完全正确。 相反，我们认为化疗耐药性可能并且经常是对任何白血病克隆中可能出现的化疗挑战的获得性表观遗传反应，我们在体外模拟了化疗耐药性，并证明 DNA 甲基化和组蛋白甲基化在化疗后迅速（几天内）发生。具体来说，H3K27me3 增加，H3K4me2 减少。为了初步研究原代细胞中表观遗传变化的贡献，我们比较了遗传和 DNA。重要的是，初步证据表明，至少 20% 的患者在复发时没有新的可检测到的基因异常，而在比较配对诊断与复发 AML 样本时，我们观察到了广泛的和复发的 AML 细胞的甲基化特征。影响特定途径的胞嘧啶甲基化的部分收敛重新分布，无论 综合起来，这些研究表明了化疗耐药的表观遗传机制，但没有解决白血病干细胞的作用。​​为了解决这个问题，我们研究了阿糖胞苷 (Ara-C) 对 NSG 小鼠异种移植的 AML 细胞的影响。重要的是，我们首次证明，Ara-C 处理的 AML 细胞的有限稀释分析并未显示 SCID 白血病起始细胞的富集。总的来说，这些数据使我们捕获了这些数据。 AML 的化疗耐药是一个生物学上复杂的事件，包括但不能完全用遗传病变来解释，并且由固定和诱导的表观遗传因素组成。为了测试和探索这些想法，我们提出了 3 个具体目标： 具体目标 1) 识别和确定。描述体外 AML 细胞对 Ara-C 的表观遗传反应的候选机制。 具体目标 2) 确定原发性 AML 患者样本中复发的表观遗传和遗传决定因素。 具体目标 3) 确定其动态和机制。白血病细胞群中出现了化学抗性特征。