Targeting high fat diet-driven DNA hypermethylation for AML chemoprevention

急性髓系白血病（AML）是一种高度侵袭性的血液恶性肿瘤， 急性白血病虽然最初看到了治疗益处，但临床结果是不可接受的。因此，癌症 预防可能是有益于AML患者的替代方法。然而，风险因素的不可用性 AML患者的早期症状阻碍了癌症预防策略的设计。越来越多的证据 表明异常DNA甲基化出现在早期AML中，并代表了合理的机制 潜在的致癌和癌性病变的起始。DNA甲基化易受以下变化的影响： 环境因素，但环境因素如何调节AML中的DNA甲基化模式 细胞不清楚。我们的初步研究表明，DNMT 1上调，DNA甲基化水平 与瘦小鼠相比，高脂饮食诱导的肥胖小鼠中， 可能在DNA甲基化的调节中起作用。我们的数据还表明，肥胖的AML患者和小鼠 患白血病的情况比瘦的人更糟，生存时间更短。虽然许多因素在 当肥胖发生改变时，IL-6，一种关键的促炎细胞因子，可能是肥胖与AML联系的主要分子。 细胞发病和疾病进展。与此一致，肥胖小鼠和患者经常与 饱和脂肪酸（SFA）的血清浓度升高，其刺激细胞因子（例如， 白介素-6（IL-6），与瘦型对应物相比。IL-6在AML细胞中也大量表达，重要的是，IL-6在AML细胞中也大量表达。 6过表达预示AML患者预后较差。用肥胖相关的IL-6蛋白治疗是 足以增加AML细胞增殖，但AML细胞中IL-6敲低显著抑制AML细胞增殖， 增长机制研究表明，IL-6蛋白促进DNMT 1的表达， DNA甲基化鉴于促炎细胞因子和异常DNA的重要作用， 由于IL-6-DNA甲基化在肿瘤发生中的作用，我们推测IL-6-DNA甲基化轴与SFA之间存在联系， 肥胖与侵袭性AML发病机制的关系。IL-6诱导DNA的药理学抑制 低甲基化并阻断AML进展。为了验证这一假设，我们提出了两个目标：1） 确定SFA异常是否以及如何增强AML白血病; 2）进行临床前体内研究 AML小鼠中IL-6抑制剂的评价。我们预期IL-6-DNA甲基化轴代表了一种新的 肥胖-癌症关联的潜在机制和AML预防的独特风险因素。我们也 预期IL-6抑制剂通过其DNA低甲基化活性抑制AML细胞的增殖， 从而作为一种实用的白血病治疗方案。

Acute myeloid leukemia (AML) is a highly aggressive hematologic malignancy and the most common adult acute leukemia. While therapeutic benefits are seen initially, clinical outcomes are unacceptable. Thus, cancer prevention could be an alternative approach to benefit AML patients. However, the unavailability of risk factors and early symptoms in AML patients hampers the design of cancer prevention strategies. Mounting evidence indicates that aberrant DNA methylation appears in early-stage AML and represents plausible mechanisms underlying initiation of carcinogenesis and cancerous lesions. DNA methylation is susceptible to change by environmental factors, but which and how environmental factors regulate DNA methylation patterning in AML cells are unclear. Our preliminary studies show that DNMT1 is upregulated and the levels of DNA methylation are increased in high-fat diet-induced obese mice compared to lean mice, supporting that lipid abnormality could play in the regulation of DNA methylation. Our data also show that obese AML patients and mice develop worse leukemic disease with a shorter survival time than lean subjects. Although many factors in obesity are altered, IL-6, a key pro-inflammatory cytokine, could be the primary molecule linking obesity to AML cell onset and disease progression. In line with this, obese mice and patients are frequently associated with elevated serum concentration of saturated fatty acids (SFA), which stimulate the secretion of cytokines (e.g., IL-6), when compared to lean counterparts. IL-6 is also abundantly expressed in AML cells, and importantly, IL- 6 overexpression predicts worse outcomes in AML patients. Treatment with obesity-relevant IL-6 protein is sufficient to increase AML cell multiplication, but IL-6 knockdown in AML cells significantly inhibits AML cell growth. Mechanistic investigation shows that IL-6 protein promotes DNMT1 expression coupled by an increase of DNA methylation. Given the important role of a pro-inflammatory cytokines and the aberrant DNA methylation in carcinogenesis and tumorigenesis, we hypothesize that IL-6-DNA methylation axis links SFA aberrations in obesity to aggressive AML pathogenesis. Pharmacological inhibition of IL-6 induces DNA hypomethylation and blocks AML progression. To test this hypothesis, we are proposing two aims: 1) To determine whether and how SFA abnormality augments AML leukemia; 2) To perform preclinical in vivo evaluation of IL-6 inhibitor in AML mice. We anticipate that IL-6-DNA methylation axis represents a novel mechanism underlying obesity-cancer association and a unique risk factor for AML prevention. We also anticipate that IL-6 inhibitor restrains the proliferation of AML cells through its DNA hypomethylating activity, and thereby, serving as a practical leukemia treatment regimen.