Interrogation of TLR2 Inflammatory Signaling in AML

AML 中 TLR2 炎症信号转导的研究

• 批准号: 10534321
• 负责人: Michael Lawler
• 金额: $ 4.68万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10534321
• 关键词: Abnormal Myeloid Cell; Acute Myelocytic Leukemia; Adult; Agonist; Blast Cell; CRISPR/Cas technology; Cell Death; Cell Differentiation process; Cell Maturation; Cell physiology; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Cessation of life; Characteristics; Clinical; Clonal Expansion; DNMT3a; DNMT3a mutation; Data; Disease; Event; FLT3 gene; Genes; Genetic Transcription; Goals; Growth; Hematologic Neoplasms; Hematopoietic; Hematopoietic stem cells; Heterogeneity; Human; ITGAM gene; Immune; Immune response; Immune signaling; Immune system; Impairment; In Vitro; Inflammatory; Innate Immune Response; Lead; Leukemic Cell; Maps; Mediating; Molecular; Mus; Mutant Strains Mice; Mutate; Mutation; Myelogenous; Myeloid Cells; Pathogenesis; Pathway interactions; Patients; Pattern; Phenotype; Phosphorylation; Population; Production; Prognosis; Publishing; Receptor Activation; Receptor Signaling; Role; Sampling; Signal Pathway; Signal Transduction; Specimen; Sum; Surface; System; TLR2 gene; Testing; Therapeutic; Therapeutic Agents; Time; Toll-like receptors; Work; acute myeloid leukemia cell; base; cell type; cytokine; directed differentiation; immune activation; in vivo; leukemia; leukemia treatment; loss of function; macrophage; monocyte; mouse model; mutant; novel; novel strategies; pathogen; progenitor; prospective; receptor; response; self-renewal; stem; stem cell function; stem-like cell; stemness; transcription factor; transcriptional reprogramming

PROJECT SUMMARY Acute myeloid leukemia (AML) is defined as a clonal expansion of abnormal myeloid blasts which are impaired to differentiate into mature and functional myeloid cells. Toll-like receptors (TLRs) are pathogen- associated molecular pattern (PAMP) receptors that specialize in recognizing foreign pathogens and elicit an innate immune response through promoting myeloid cell differentiation and inflammatory cytokine production. The role of TLR signaling in AML is poorly understood, and the mechanisms involved in an innate immune response through TLRs, and whether this induces differentiation and/or cell death of AML blasts is unclear. Two of the most commonly mutated genes in AML are FLT3 and DNMT3A, where 20% of AML patients can be found with co-occurring mutations, which results in a poor prognosis. Preliminary data indicate that TLRs are expressed on the surface of AML cells, and stimulation of these receptors produces a proinflammatory response associated with AML blast differentiation. In sum, I identify, in DNMT3A-mutant AML, a TLR signaling network that regulates differentiation of AML and increases the survival of this common and clinically poor AML subtype which can lead to a prospectively new differentiating/therapeutic agent for AML treatment.

项目摘要 急性髓性白血病（AML）定义为异常髓性母细胞的克隆性扩增， 分化为成熟和功能性骨髓细胞受损。Toll样受体（TLR）是病原体- 相关分子模式（PAMP）受体，专门识别外来病原体，并引发 通过促进骨髓细胞分化和炎性细胞因子产生的先天免疫应答。 TLR信号传导在AML中的作用知之甚少，先天免疫应答中涉及的机制 目前尚不清楚这是否通过TLR诱导AML母细胞的分化和/或细胞死亡。两 AML中最常见的突变基因是FLT 3和DNMT 3A，其中20%的AML患者可以发现 同时发生突变导致预后不良初步数据表明，TLR表达 在AML细胞表面，刺激这些受体会产生相关的促炎症反应 AML原始细胞分化。总之，我在DNMT 3A突变型AML中鉴定了一个TLR信号网络， AML的分化，并增加这种常见的和临床上较差的AML亚型的生存率， 涉及用于AML治疗的前瞻性新分化/治疗剂。