Targeting high fat diet-driven DNA hypermethylation for AML chemoprevention

针对高脂肪饮食驱动的 DNA 高甲基化进行 AML 化学预防

基本信息

批准号：
9172103
负责人：
Shujun Liu
金额：
$ 7.75万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9172103
关键词：
Aberrant DNA Methylation Acute Myelocytic Leukemia Acute leukemia Adult Behavior Cancerous Cell Proliferation Cells Chemoprevention Clinical Consumption Coupled DNA DNA Methylation DNA Methylation Regulation DNA Modification Methylases DNA Sequence Alteration DNMT3B gene Data Development Disease Disease Progression Environmental Risk Factor Epigenetic Process Evaluation Event Functional disorder Gene Silencing Goals Growth Hematologic Neoplasms High Fat Diet Hypermethylation In Vitro Inflammation Inflammatory Intake Interleukin-15 Interleukin-6 Investigation Lesion Link Lipids Malignant Neoplasms Measures Mediating Modality Molecular Mus Normal Cell Obese Mice Obesity Oncogenes Outcome Pathogenesis Pathway interactions Patients Phase Physiological Play Positioning Attribute Prevention Prevention strategy Production Proteins Regimen Research Personnel Risk Factors Role Saturated Fatty Acids Serum Staging Symptoms Testing Therapeutic Time Treatment Protocols Tumor Suppressor Genes Up-Regulation adult leukemia base cancer prevention cancer risk cancer type carcinogenesis cell growth cytokine design disorder prevention efficacy testing in vivo inhibitor/antagonist knock-down leukemia leukemia treatment methylation pattern neoplastic cell novel novel chemoprevention novel strategies overexpression pre-clinical prevent promoter tumor tumorigenesis

项目摘要

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.

急性髓系白血病（AML）是一种高度侵袭性的血液恶性肿瘤，也是最常见的成人疾病急性白血病。虽然最初可以看到治疗效果，但临床结果却令人无法接受。因此，癌症预防可能是使 AML 患者受益的另一种方法。然而，缺乏危险因素 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，并且代表了合理的机制癌发生和癌性病变的潜在起始。 DNA甲基化很容易被改变环境因素，但哪些环境因素以及如何调节 AML 中的 DNA 甲基化模式细胞不清楚。我们的初步研究表明 DNMT1 上调并且 DNA 甲基化水平与瘦小鼠相比，高脂肪饮食诱导的肥胖小鼠的血脂水平有所增加，这支持了脂质异常可能在DNA甲基化的调控中发挥作用。我们的数据还表明，肥胖的 AML 患者和小鼠与瘦人相比，他们会患上更严重的白血病，且生存时间更短。虽然因素很多肥胖发生改变，IL-6（一种关键的促炎细胞因子）可能是将肥胖与 AML 联系起来的主要分子细胞发病和疾病进展。与此相符，肥胖小鼠和患者经常与饱和脂肪酸（SFA）的血清浓度升高，刺激细胞因子的分泌（例如， IL-6），与精益对应物相比。 IL-6 在 AML 细胞中也大量表达，重要的是，IL-6 6 过度表达预示着 AML 患者的预后较差。使用与肥胖相关的 IL-6 蛋白进行治疗是足以增加 AML 细胞增殖，但 AML 细胞中的 IL-6 敲低会显着抑制 AML 细胞生长。机制研究表明 IL-6 蛋白通过增加 DNMT1 表达来促进 DNMT1 表达 DNA甲基化。鉴于促炎细胞因子和异常 DNA 的重要作用甲基化在癌变和肿瘤发生中的作用，我们假设 IL-6-DNA 甲基化轴与 SFA 相关肥胖异常导致侵袭性 AML 发病机制。 IL-6 的药理学抑制诱导 DNA 低甲基化并阻止 AML 进展。为了检验这个假设，我们提出两个目标：1）确定 SFA 异常是否以及如何加重 AML 白血病； 2) 进行临床前体内试验 IL-6抑制剂在AML小鼠中的评价。我们预计 IL-6-DNA 甲基化轴代表了一种新的肥胖与癌症关联的潜在机制和预防 AML 的独特危险因素。我们也预计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。