Genetic and epigenetic basis of relapse in acute myeloid leukemia

急性髓系白血病复发的遗传和表观遗传基础

• 批准号: 8535705
• 负责人: Francine Evalina Garrett-Bakelman
• 金额: $ 14.83万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8535705
• 关键词: Acute Myelocytic Leukemia; Address; Affect; Age; Biological; Biological Assay; Cell physiology; Cells; Clinical; Clinical Management; Clonal Evolution; Cytosine; Cytotoxic agent; DNA; DNA Methylation; Data; Detection; Diagnosis; Disease; Disease Progression; Enrollment; Epigenetic Process; Event; Exposure to; Foundations; Funding; Gene Expression Profile; Gene Expression Regulation; Gene Mutation; Genetic; Genetic Determinism; Genome; Genomics; Goals; Grant; High Dose Chemotherapy; Incidence; Laboratories; Lesion; Leukemic Cell; Malignant Neoplasms; Mediating; Mentors; Methods; Methylation; Molecular; Mutation; Myelogenous; Natural Selections; Outcome; Pathway interactions; Patients; Pattern; Phase II Clinical Trials; Phenotype; Play; Process; Property; Recurrence; Recurrent disease; Relapse; Relative (related person); Research; Resistance; Risk; Role; Sampling; Series; Solid Neoplasm; Specimen; Stem cells; Stereotyping; Surface; Techniques; Testing; The Cancer Genome Atlas; Therapeutic Intervention; Treatment Failure; United States National Institutes of Health; Validation; base; chemotherapy; clinically relevant; clinically significant; cohort; deep sequencing; design; epigenomics; experience; genome-wide; improved; in vitro Assay; in vivo; leukemia; leukemic stem cell; loss of function; methylome; novel; outcome forecast; prevent; response; theories; transcriptomics

DESCRIPTION (provided by applicant): Acute myeloid leukemia (AML) is a genetically heterogeneous disease, which occurs de novo or evolves from pre-existing myeloid disorders. The incidence of AML increases with age, and with increasing age, prognosis and overall survival decline. Treatment failure in many patients is attributed to relapsed disease and remains the fundamental clinical challenge in these patients. The exact biological basis of relapse remains unclear. One prevailing theory is that inherently chemotherapy resistant leukemia stem cells (LSCs) survive and repopulate the disease. However genetic background must also have an influence on LSC functions since specific mutations are associated with more frequently relapsing disease. It has also been observed that AMLs undergo clonal evolution with relapse, suggesting that pre-existing subclones or chemotherapy induced natural selection contribute to this phenomenon. Our preliminary data strongly suggest that epigenetic mechanisms play a fundamental role in this process. Specifically: i) we observe extensive epigenetic deregulation in all AML patients, ii) specific epigenetic signatures and classifiers are associated with poor outcomes, iii) there is a relative paucity of genetic mutations in AML as compared to solid tumors (based on TCGA data), iv) many of the common genetic lesions in AML directly alter epigenetic gene regulation. Moreover in preliminary studies we observe that AMLs at relapse display large scale epigenetic changes, whereas TCGA finds relatively subtle genetic changes at relapse. Of note, many of the epigenetic changes we observe are in common between patients, suggesting that AMLs may respond and resist chemotherapy using shared or stereotyped mechanisms. Based on these and other considerations we hypothesize that AML relapse and adaptation to chemotherapy is encoded by a combination of epigenetic and genetic lesions that are either present in a subset of AML cells at diagnosis or occur de novo in response to exposure to cytotoxic drugs. We predict that these lesions preferentially disrupt specific biological pathways that directly mediate chemotherapy resistance, and that detection of these lesions at diagnosis will be predictive of unfavorable outcome. In order to test these hypotheses we will perform a genome wide integrative genetic and epigenetic comparison of seventy matched diagnosis/relapse AML specimens including the use of novel methods developed by the applicant. Results will be validated, and the clinical significance determined in an independent cohort of 750 patients all enrolled in a single phase II clinical trial. The biologial function of relapse-associated lesions will be confirmed in functional assays, with the ultimate goal of developing targeted therapies to prevent leukemia relapse.

描述（由申请人提供）：急性髓性白血病（AML）是一种遗传异质性疾病，其新发或从既存髓性疾病演变而来。AML的发病率随着年龄的增长而增加，随着年龄的增长，预后和总生存期下降。许多患者的治疗失败归因于疾病复发，并且仍然是这些患者的基本临床挑战。复发的确切生物学基础尚不清楚。一个流行的理论是，固有的化疗耐药性白血病干细胞（LSC）存活并重新繁殖疾病。然而，遗传背景也必须对LSC功能有影响，因为特定的突变与更频繁复发的疾病有关。还观察到AML经历克隆进化并复发，表明预先存在的亚克隆或化疗诱导的自然选择促成了这种现象。我们的初步数据有力地表明，表观遗传机制在这一过程中发挥了重要作用。具体而言：i）我们在所有AML患者中观察到广泛的表观遗传失调，ii）特定的表观遗传特征和分类器是 与不良结局相关，iii）与实体瘤相比，AML中的基因突变相对较少（基于TCGA数据），iv）AML中的许多常见遗传病变直接改变表观遗传基因调控。此外，在初步研究中，我们观察到AML复发时显示大规模的表观遗传变化，而TCGA发现复发时相对微妙的遗传变化。值得注意的是，我们观察到的许多表观遗传学变化在患者之间是共同的，这表明AML可能使用共享或定型的机制来响应和抵抗化疗。基于这些和其他考虑，我们假设AML复发和对化疗的适应是由表观遗传和遗传病变的组合编码的，这些病变在诊断时存在于AML细胞亚群中，或者在暴露于细胞毒性药物后重新发生。我们预测这些病变优先破坏直接介导化疗耐药的特定生物学途径，并且在诊断时检测这些病变将预测不利的结果。为了测试 在这些假设中，我们将对70个匹配的诊断/复发AML样本进行全基因组整合遗传和表观遗传比较，包括使用申请人开发的新方法。将对结果进行验证，并在750例患者的独立队列中确定临床意义，这些患者均参加了一项II期临床试验。复发相关病变的生物学功能将在功能测定中得到证实，最终目标是开发靶向治疗以预防白血病复发。