Hyperglycemia mediated myeloproliferative disease

高血糖介导的骨髓增生性疾病

• 批准号: 10386813
• 负责人: Reuben Kapur
• 金额: $ 58.28万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10386813
• 关键词: Abnormal Myeloid Cell; Acute; Acute Myelocytic Leukemia; Alleles; Anti-Inflammatory Agents; Apoptotic; Biological; Blood Cells; Bone Marrow; Cells; Chronic; Chronic Myelomonocytic Leukemia; Cytokine Signaling; Cytosine; DNA; DNA Methylation; Data; Defect; Development; Diabetes Mellitus; Diabetic mouse; Dioxygenases; Disease; Disease Progression; Epidemiology; Epigenetic Process; Exposure to; Frequencies; Gene Expression; Genes; Genetic; Glucose; Growth; Hematologic Neoplasms; Hematology; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Heme; Heterozygote; Human; Hyperglycemia; Immune; Impairment; Individual; Inflammation; Inflammatory; Interleukin-6; Knowledge; Lesion; Ligands; Malignant Neoplasms; Mediating; Methyltransferase; Mononuclear; Mus; Mutate; Mutation; Myeloid Leukemia; Myeloproliferative disease; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Persons; Pharmacology; Phenotype; Phosphorylation; Prognosis; Protein Family; Proteins; Race; Recurrence; Risk Factors; Role; S100A8 gene; S100A9 gene; Series; Serine; Signal Transduction; Stress; TLR4 gene; Testing; Tumor Suppressor Proteins; Up-Regulation; adenylate kinase; age related; aged; base; diabetic; diabetic patient; exome sequencing; feeding; hematopoietic stem cell self-renewal; innovation; leukemia; leukemogenesis; loss of function; mouse model; novel; overexpression; peripheral blood; response; stem cells

PROJECT SUMMARY/ABSTRACT Diabetes mellitus (DM) is a strong risk factor for cancer development. However, it is unclear if DM is also a risk factor for transforming pre-leukemic stem cells (pre-LSCs) into full-blown leukemia such as acute myeloid leukemia (AML), chronic myelomonocytic leukemia (CMML) or severe form of myeloproliferative neoplasm (MPN). To this end, extensive whole exome sequencing on peripheral blood (PB) cells of more than 20 thousand persons who were unselected for hematologic phenotypes were examined for 160 genes that are recurrently mutated in leukemia. Two most mutated genes found were epigenetic regulators: Ten eleven translocation methylcytosine dioxygenase 2 (TET2) and DNA cytosine-methyltransferase 3A (DNMT3A). Notably, both these genes are mutated at very high frequency in patients with MPNs and AML. Importantly, epidemiological findings demonstrate that persons with DM are more likely to have these mutations than those without DM. However, there is a significant gap in knowledge regarding our understanding of DMs causative role in MPN and leukemogenesis. Studies using murine models of loss of Tet2 function (Tet2-/-) show that Tet2-deficient hematopoietic stem cells (HSCs) have abnormal global 5-hydroxymethylcytosine (5-hmC) levels and local 5- hmC levels in genes responsible for self-renewal of HSCs. In addition, Tet2-/- HSCs show a competitive advantage (i.e. clonal hematopoiesis) over normal HSCs but do not progress to AML development. Moreover, mice with haplo-insufficiency of Tet2 (Tet2+/-) manifest milder form of these phenotypes only when aged, indicating that Tet2 functions as a putative tumor suppressor. We discovered that Tet2-deficient mice manifest a sustained response to acute inflammation and aged naïve Tet2-/- mice show elevated expression of a series of genes encoding the innate immune/pro-inflammatory pathway components including S100A8/9, TLR4, NFκB1 and IL-6. As patients with DM develop chronic inflammation and have increased expression of S100A8/A9, the central hypothesis of this proposal is that diabetic individuals that carry a single genetic lesion in the form of TET2 in their HSCs (in absence of any hematologic malignancies), will be more susceptible to developing severe MPN and/or myeloid leukemia, in part to an overactive pro-inflammatory cytokine signaling cascade or a forward feeding positive signaling loop and in part to hyperglycemia (HG) induced further global reduction in 5-hmC levels in pre-LSCs bearing loss of Tet2, thus mimicking pre-LSCs lacking all forms of TET. Indeed, by introducing Tet2 mutation into a murine model of diabetes (Ins2Akita/+), our preliminary data demonstrate that the diabetic mice haploinsufficient for Tet2 (Ins2Akita/+;Tet2+/-) progressively develop lethal AML/severe MPN. Importantly, treatment of Tet2-/- mice exposed to an acute inflammatory challenge with an anti-inflammatory molecule, APX3330, reverses this phenotype. Based on these preliminary results, we hypothesize that progressive DM acts as a significant risk factor for transforming pre-LSCs and/or clonal hematopoiesis into heme malignancies in an age-dependent manner.

项目概要/摘要 糖尿病（DM）是癌症发展的一个强烈危险因素。然而，尚不清楚 DM 是否也是一种风险 将白血病前干细胞 (pre-LSC) 转化为成熟白血病（例如急性髓系白血病）的因子 白血病 (AML)、慢性粒单核细胞白血病 (CMML) 或严重的骨髓增生性肿瘤 （MPN）。为此，对 2 万多个外周血 (PB) 细胞进行了广泛的全外显子组测序 对未进行血液学表型选择的人进行了 160 个经常性基因检查 在白血病中发生突变。发现的两个突变最多的基因是表观遗传调节因子：十一个十一易位 甲基胞嘧啶双加氧酶 2 (TET2) 和 DNA 胞嘧啶甲基转移酶 3A (DNMT3A)。值得注意的是，这两个 MPN 和 AML 患者的基因突变频率非常高。重要的是，流行病学调查结果 证明患有糖尿病的人比没有糖尿病的人更有可能患有这些突变。然而， 我们对 DM 在 MPN 中的致病作用的理解存在重大差距， 白血病发生。使用 Tet2 功能丧失 (Tet2-/-) 的小鼠模型进行的研究表明，Tet2 缺陷 造血干细胞 (HSC) 的整体 5-羟甲基胞嘧啶 (5-hmC) 水平和局部 5-羟甲基胞嘧啶 (5-hmC) 水平异常 负责 HSC 自我更新的基因中的 hmC 水平。此外，Tet2-/- HSC 表现出竞争性 与正常 HSC 相比具有优势（即克隆造血），但不会发展为 AML。而且， Tet2 (Tet2+/-) 单倍体不足的小鼠仅在衰老时才会表现出较温和的表型， 表明 Tet2 具有假定的肿瘤抑制因子的功能。我们发现 Tet2 缺陷小鼠表现出 对急性炎症的持续反应和老年幼稚 Tet2-/- 小鼠表现出一系列表达升高 编码先天免疫/促炎通路成分的基因，包括 S100A8/9、TLR4、NFκB1 和IL-6。随着 DM 患者出现慢性炎症并且 S100A8/A9 表达增加， 该提案的中心假设是，携带单一遗传病变的糖尿病个体 HSC 中的 TET2（在没有任何血液恶性肿瘤的情况下）将更容易发展为严重的 MPN 和/或骨髓性白血病，部分原因是过度活跃的促炎细胞因子信号级联或前向 喂养正信号环路并部分导致高血糖 (HG) 诱导 5-hmC 进一步全面减少 前LSCs中Tet2缺失的水平，从而模仿了缺乏所有形式TET的前LSCs。确实，通过介绍 Tet2突变进入糖尿病小鼠模型（Ins2Akita/+），我们的初步数据表明，糖尿病小鼠 Tet2 单倍体不足的小鼠 (Ins2Akita/+;Tet2+/-) 逐渐发展为致命的 AML/严重 MPN。重要的是， 用抗炎分子治疗暴露于急性炎症挑战的Tet2-/-小鼠， APX3330，逆转了这种表型。根据这些初步结果，我们假设进行性 DM 作为将前 LSC 和/或克隆造血转化为血红素恶性肿瘤的重要危险因素 以与年龄相关的方式。