Integration of epigenetic and non-coding RNA mechanisms in leukemia

摘要 急性髓性白血病（AML）是所有白血病中最常见的（30-40%），生存率最低（25%） 任何白血病。DNA甲基转移酶DNMT 3A突变和FLT 3的内部串联重复 受体酪氨酸激酶（FLT 3-ITD），是超过50%的AML中最常见的两种事件， 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。 急性髓细胞白血病DNMT 3A/FLT 3突变型AML的不良临床结局比单独突变的AML更严重。 因此，迫切需要更好地了解这种疾病的生物学机制， 应对紧迫的治疗挑战。我们的初步数据表明，DNMT 3A/FLT 3-ITD AML 通过Toll样受体（TLR）下调先天免疫信号传导，以维持干性和阻断 分化我们的数据还表明，microRNA可能在TLR的失调中发挥重要作用。 在AML细胞中的信号通路，表明表观遗传/信号突变，microRNA， AML中的先天免疫信号传导。尽管有证据表明TLR信号传导是导致肿瘤细胞凋亡的重要因素， 尽管AML是骨髓增生异常综合征（MDS）的主要发病机制，但对AML中TLR信号传导知之甚少。因此我们 正在致力于定义AML中TLR信号失调的机制，了解 TLR信号传导抑制在AML发病机制中的后果，以及最终TLR信号传导是否可以被抑制 用于治疗AML。

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.