Epigenetic biomarkers of response to Azacytidine in Myelodysplastic Syndromes

骨髓增生异常综合征中氮胞苷反应的表观遗传生物标志物

• 批准号: 9268794
• 负责人: Maria Eugenia Figueroa
• 金额: $ 39.04万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9268794
• 关键词: Acute Myelocytic Leukemia; Age; Algorithms; Alternative Therapies; Azacitidine; Biological; Biological Assay; Biological Markers; Bone Marrow; Characteristics; Chemotherapy-Oncologic Procedure; Chronic Myelomonocytic Leukemia; Classification; Clinical; CpG Islands; DNA; DNA Methylation; DNA Methyltransferase Inhibitor; Data; Decitabine; Development; Diagnosis; Disease; Disease Management; Distal; Drug resistance; Dysmyelopoietic Syndromes; Elderly; Enhancers; Epigenetic Process; Exons; Gene Expression; Gene Expression Profile; Gene Mutation; Genetic Transcription; Genome; Genomics; Hematological Disease; Hematopoiesis; Hypercellular Bone Marrow; Hypermethylation; ITGB3 gene; Ineffective Hematopoiesis; Introns; Lead; Machine Learning; Massive Parallel Sequencing; Molecular; Molecular Profiling; Mutation Analysis; Nucleic Acid Regulatory Sequences; PPBP gene; Pancytopenia; Patients; Play; Promoter Regions; Regimen; Resistance; Risk; Role; Specimen; Syndrome; Technology; Time; Translating; Validation; base; bisulfite sequencing; chemotherapy; clinical biomarkers; cohort; cytopenia; differential expression; effective therapy; epigenetic marker; epigenome; epigenomics; genome-wide; genome-wide analysis; in vivo; ineffective therapies; molecular diagnostics; molecular marker; next generation; next generation sequencing; novel; overexpression; patient stratification; peripheral blood; predicting response; predictive marker; prevent; public health relevance; responders and non-responders; response; response biomarker; therapeutic target; therapy resistant; transcriptome sequencing; treatment response; unnecessary treatment

 DESCRIPTION (provided by applicant): Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal blood disorders characterized by ineffective hematopoiesis that can lead to bone marrow failure and progression to acute myeloid leukemia (AML). Aberrant DNA hypermethylation is characteristic of this disorder and, as such, DNA methyltransferase inhibitors (DMTis) are often used to treat MDS in lieu of conventional chemotherapies that have proven to be ineffective for this disease. However, even with DMTi therapy, only about one third of MDS patients achieve a clinical response leading to a survival benefit. Moreover, current DMTi-based regimens for MDS require a minimum of 6 months of treatment before a patient can be deemed resistant to this therapy. Given that only ~30-40% of patients respond to this treatment, the majority of patients will spend 6 months receiving a therapy to which they are unlikely to respond. Therefore, the identification of molecular differences that distinguish between sensitive and resistant patients at the time of diagnosis is critical in order to harness these differences for the development of molecular biomarkers predictive of DMTi response. These biomarkers would allow us to more accurately risk-stratify these patients and prevent unwarranted and ineffective therapy for resistant patients. Using next-generation sequencing technology we performed genome-wide DNA methylation, gene expression and mutational analysis on a cohort of patients with chronic myelomonocytic leukemia (CMML), an MDS/MPN overlap syndrome, including both sensitive and resistant patients to the DMTi Decitabine (DAC). We found that robust epigenetic and gene expression differences exist between DMTi responders and non-responders. From these differences, we were able to develop an epigenetic classifier that predicts response to decitabine therapy in these patients with 87% accuracy. Moreover, using RNA-seq we identified a gene expression signature associated with primary resistance to DAC in CMML. Based on these data, we hypothesize that comparable differences are likely to be found in MDS patients who are either sensitive or resistant to the DMTi Azacytidine (AZA), and that these too have the potential to be used as the basis of a molecular classifier of response as well as to identify mechanisms of primary resistance to the drug. We propose to perform genome-wide studies DNA methylation and expression studies in a cohort of 250 MDS patients treated with AZA in order to identify DNA methylation and expression biomarkers predictive of response to this agent in MDS. From these studies, we expect to be able to develop clinically useful biomarkers that can be translated to CLIA-compatible technologies that can be applied in molecular diagnostics labs.

 描述（由申请人提供）：骨髓增生异常综合征（MDS）是一组异质性克隆性血液疾病，其特征是无效造血，可导致骨髓衰竭并进展为急性髓系白血病（AML）。异常的 DNA 高甲基化是这种疾病的特征，因此，DNA 甲基转移酶抑制剂 (DMTis) 通常用于治疗 MDS，以代替已被证明对这种疾病无效的传统化疗。然而，即使采用 DMTi 治疗，也只有约三分之一的 MDS 患者达到临床缓解，从而获得生存获益。此外，目前基于 DMTi 的 MDS 治疗方案需要至少 6 个月的治疗才能认为患者对该疗法具有抵抗力。鉴于只有约 30-40% 的患者对这种治疗有反应，大多数患者将花费 6 个月的时间接受他们不太可能产生反应的治疗。因此，在诊断时识别区分敏感和耐药患者的分子差异至关重要，以便利用这些差异来开发预测 DMTi 反应的分子生物标志物。这些生物标志物将使我们能够更准确地对这些患者进行风险分层，并防止对耐药患者进行不必要和无效的治疗。利用新一代测序技术，我们对一组慢性粒单核细胞白血病 (CMML)（一种 MDS/MPN 重叠综合征）患者进行了全基因组 DNA 甲基化、基因表达和突变分析，其中包括对 DMTi 地西他滨 (DAC) 敏感和耐药的患者。我们发现 DMTi 应答者和非应答者之间存在显着的表观遗传和基因表达差异。根据这些差异，我们能够开发出一种表观遗传分类器，可以预测这些患者对地西他滨治疗的反应，准确度为 87%。此外，使用 RNA-seq，我们确定了与 CMML 中 DAC 初级抗性相关的基因表达特征。基于这些数据，我们假设在对 DMTi 氮杂胞苷 (AZA) 敏感或耐药的 MDS 患者中可能会发现类似的差异，并且这些差异也有可能用作反应分子分类器的基础以及确定对该药物的主要耐药机制。我们建议对 250 名接受 AZA 治疗的 MDS 患者进行全基因组 DNA 甲基化和表达研究，以确定可预测 MDS 对该药物反应的 DNA 甲基化和表达生物标志物。通过这些研究，我们期望能够开发出临床上有用的生物标志物，这些生物标志物可以转化为可应用于分子诊断实验室的 CLIA 兼容技术。