Interrogation of TLR2 Inflammatory Signaling in AML

项目总结 急性髓系白血病(AML)被定义为异常髓系原始细胞的克隆性扩张 不能分化为成熟的和有功能的髓系细胞。Toll样受体是一种病原体- 相关分子模式(PAMP)受体，专门识别外来病原体并诱导 通过促进髓系细胞分化和炎性细胞因子产生的先天免疫反应。 TLR信号在AML中的作用知之甚少，而涉及先天免疫的机制也不清楚 通过TLRs的反应，这是否诱导AML细胞分化和/或细胞死亡尚不清楚。二 AML中最常见的突变基因是Flt3和DNMT3A，20%的AML患者可以在这些基因中找到 有共生突变，这会导致不良预后。初步数据表明，TLRs被表达 在AML细胞表面，这些受体的刺激会产生与之相关的促炎反应 伴AML原始细胞分化。总之，我在DNMT3A突变AML中发现了一个TLR信令网络，它调节 AML的分化，并增加这种常见的和临床上较差的AML亚型的存活率 一种有望成为治疗AML的新型分化/治疗剂。

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.