Integration of epigenetic and non-coding RNA mechanisms in leukemia

表观遗传和非编码 RNA 机制在白血病中的整合

基本信息

批准号：
10198862
负责人：
Sara E Meyer
金额：
$ 35.69万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10198862
关键词：
Acute Myelocytic Leukemia Address Adult Affect Agonist Biological CXCL9 gene Characteristics Chemoresistance Child Clinical Clustered Regularly Interspaced Short Palindromic Repeats Cytotoxic Chemotherapy DNA DNA Methylation DNA Modification Methylases DNMT3a Data Dependence Development Disease Dysmyelopoietic Syndromes Epigenetic Process Event Exhibits FLT3 gene Gene Expression Gene Expression Profile Gene Expression Regulation Genes Genetic Transcription Growth Hematopoietic Neoplasms Hematopoietic stem cells Human IRAK4 gene Immune signaling Lead Maintenance Messenger RNA Methyltransferase MicroRNAs Mus Mutation Myelogenous Outcome Output Pathogenesis Patients Phosphotransferases Play RELA gene Receptor Protein-Tyrosine Kinases Receptor Signaling Regulator Genes Resistance Role Signal Transduction TLR7 gene Testing Therapeutic Toll-Like Receptor Pathway Toll-like receptors Untranslated RNA Work acute myeloid leukemia cell cell growth chemokine chemotherapy cytokine genomic locus high risk in vivo innovation leukemia leukemia initiating cell leukemia treatment leukemic stem cell leukemic transformation leukemogenesis loss of function mouse model mutant novel novel therapeutics overexpression prognostic restoration self-renewal standard care stemness therapeutic evaluation treatment response

项目摘要

ABSTRACT Acute myeloid leukemia (AML) is the most common (30-40%) of all leukemias and has the poorest survival (25%) of any leukemia. Mutations in the DNA methyltransferase DNMT3A and internal tandem duplications of the FLT3 receptor tyrosine kinase (FLT3-ITD) and are two of the most frequent events in over 50% of AML and commonly co-occur in patients conferring increased resistance to chemotherapy, the standard treatment for this subtype of AML. DNMT3A/FLT3-mutant AML have more adverse clinical outcome than AML with either mutation alone. Thus, there is a dire need for a better understanding of the biological mechanisms underlying this disease to address pressing therapeutic challenges. Our preliminary data suggest that DNMT3A/FLT3-ITD AML downregulate innate immune signaling through Toll-like receptors (TLRs) to maintain stemness and block differentiation. Our data also indicate that microRNA may play an important role in the dysregulation of TLR pathways in AML cells, suggesting a novel crosstalk between epigenetic/signaling mutations, microRNA, and innate immune signaling in AML. Despite evidence that suggests TLR signaling is an important contributor to the pathogenesis of myelodysplastic syndrome (MDS), very little is known about TLR signaling in AML. Thus, we are focusing on defining the mechanisms that deregulate TLR signaling in AML, understanding the consequences of suppressed TLR signaling in AML pathogenesis, and finally whether TLR signaling can be leveraged to treat AML.

抽象的急性髓样白血病（AML）是所有白血病中最常见的（30-40％），生存率最差（25％）任何白血病。 DNA甲基转移酶DNMT3A的突变和FLT3的内部串联重复受体酪氨酸激酶（FLT3-ITD）是超过50％的AML和通常的两个事件同时发生的患者对化学疗法的抵抗力增加，这是该亚型的标准治疗方法 AML。 DNMT3A/FLT3突变AML比仅具有任何突变的AML具有更多的不良临床结果。因此，迫切需要更好地了解该疾病的生物学机制解决紧迫的治疗挑战。我们的初步数据表明DNMT3A/FLT3-ITD AML 通过Toll样受体（TLR）下调先天免疫信号传导以保持茎和阻塞分化。我们的数据还表明，microRNA可能在TLR的失调中起重要作用 AML细胞中的途径，表明表观遗传/信号传导突变，microRNA和 AML中的先天免疫信号传导。尽管有证据表明TLR信号传导是造成这种情况的重要因素骨髓增生综合征（MDS）的发病机理，关于AML中TLR信号传导知之甚少。因此，我们专注于定义放大AML中TLR信号的机制，了解 AML发病机理中抑制TLR信号传导的后果，最后是否可以TLR信号传导杠杆来治疗AML。