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: 9295847
• 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/9295847
• 关键词: Acute Myelocytic Leukemia; Address; Affect; Aftercare; Anthracyclines; Ara-C; Azacitidine; BCL6 gene; Biological; Cells; Chemosensitization; Clinical; Complex; Cytarabine; Cytosine; DNA Methyltransferase Inhibitor; Dangerousness; Data; Diagnosis; Disease; Down-Regulation; EZH2 gene; Elements; Enzymes; Epigenetic Process; Event; Exons; Gene Targeting; Genes; Genetic; Genetic Determinism; Genetic Transcription; HDAC9 gene; Hematopoietic Neoplasms; Histone-Lysine N-Methyltransferase; Histones; Human; In Vitro; KDM1A gene; Lead; Lesion; Leukemic Cell; Methylation; Modeling; Molecular; Molecular Abnormality; Mus; Mutation; Pathway interactions; Patients; Phenotype; Population; Property; Regulation; Relapse; Resistance; Role; Sampling; Specimen; Stress; Testing; Time; Up-Regulation; Xenograft procedure; chemotherapy; cohort; genetic disorder diagnosis; genetic signature; histone methylation; in vivo; inhibitor/antagonist; leukemia; leukemic stem cell; mortality; novel; public health relevance; 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（由适用提供）：抗化疗性是治疗急性髓样白血病（AML）患者的最重要的临床挑战。大多数AML患者最初对化学疗法有反应，但超过一半的反应者会中继并最终死于疾病。传统上，假设化学疗法耐药性代表具有白血病干细胞（LSC）特性的一般不同克隆的选择。最近的 数据和我们的初步结果（下）表明该模型的一部分都不完全正确。 相反，我们认为化学疗法耐药性可以并且经常是对任何白血病克隆中可能出现的对化学治疗挑战的获得的表观遗传反应。在体外，我们对化学疗法的耐药性进行了建模，并证明了用ARA-C处理后，DNA甲基化和组蛋白甲基化迅速改变（几天之内）。具体而言，H3K27ME3增加，H3K4ME2降低。为了最初研究原代细胞表观遗传变化的贡献，我们比较了诊断和缓解时140对AML细胞的遗传和DNA甲基化特征。重要的是，初步证据表明，至少有20％的患者在缓解时没有新的可检测到的遗传异常。相反，当比较配对诊断与浮雕AML标本时，我们会观察到胞质甲基化的广泛而部分收敛的重新分布，影响特定途径 遗传背景。共同处理这些研究表明了化学疗法抗性的表观遗传机制，但没有解决白血病干细胞的作用。为了解决这个问题，我们研究了胞嘧啶阿拉伯糖苷（ARA-C）对NSG小鼠中异种移植的影响。重要的是，我们首次证明了对ARA-C治疗AML细胞的限制稀释分析并未显示出启动的SCID-白细胞中的富集。总的来说，这些数据使我们假设AML中的化学疗法耐药性是一个生物学上复杂的事件，其中包括但并未通过遗传病变来完全解释，并且由固定和诱导的表观遗传元素组成。为了测试和探索这些思想，我们提出了3个具体目的：具体目的1）识别和表征体外AML细胞中表观遗传学反应的候选机制。具体目的2）确定原代AML患者样品中缓解的表观遗传和遗传决定因素。特定目标3）确定白血病细胞种群中化学抗性特征的动力学和机制。