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 急性髓样白血病（AML）被定义为异常髓样爆炸的克隆膨胀 障碍会分化为成熟和功能性髓样细胞。电话样受体（TLR）是病原体 相关的分子模式（PAMP）受体，专门识别异物病原体并引起 先天免疫反应通过促进髓样细胞分化和炎性细胞因子产生。 TLR信号在AML中的作用鲜为人知，与先天免疫有关的机制 通过TLR的响应以及这种诱导AML爆炸的分化和/或细胞死亡尚不清楚。二 AML中最常见的突变基因是FLT3和DNMT3A，其中有20％的AML患者被发现 随着共同发生的突变，预后不良。初步数据表明TLR是表达的 在AML细胞的表面上，这些受体的刺激会产生促炎反应相关的反应 与AML爆炸分化。总而言之，我在DNMT3A突变AML中识别一个调节的TLR信号网络 AML的分化并增加了这种常见和临床上差的AML亚型的存活率 到前瞻性的新区分/治疗剂进行AML治疗。