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

• 批准号: 10442752
• 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
• 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/10442752
• 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; DNMT3a mutation; 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

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 急性髓系白血病 (AML) 是所有白血病中最常见的 (30-40%)，且生存率最差 (25%) 任何白血病。 DNA 甲基转移酶 DNMT3A 突变和 FLT3 内部串联重复 受体酪氨酸激酶 (FLT3-ITD) 是 50% 以上 AML 中最常见的两个事件，通常 同时发生在对化疗耐药性增加的患者中，化疗是这种亚型的标准治疗方法 反洗钱。 DNMT3A/FLT3 突变型 AML 比仅具有任一突变的 AML 具有更不良的临床结果。 因此，迫切需要更好地了解这种疾病的生物学机制，以 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，以维持干性并阻断 差异化。我们的数据还表明 microRNA 可能在 TLR 失调中发挥重要作用 AML 细胞中的通路，表明表观遗传/信号突变、microRNA 和 AML 中的先天免疫信号传导。尽管有证据表明 TLR 信号传导是导致 骨髓增生异常综合征 (MDS) 的发病机制，对于 AML 中的 TLR 信号传导知之甚少。因此，我们 专注于定义在 AML 中解除 TLR 信号传导的机制，了解 TLR 信号传导抑制在 AML 发病机制中的后果，以及最后 TLR 信号传导是否可以被抑制 用于治疗 AML。