Hyperglycemia mediated myeloproliferative disease

高血糖介导的骨髓增生性疾病

• 批准号: 9899320
• 负责人: Reuben Kapur
• 金额: $ 57.78万
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899320
• 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; 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; outcome forecast; 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.

项目摘要/摘要 糖尿病（DM）是癌症发展的强大危险因素。但是，目前尚不清楚DM是否也是风险 将白血病前干细胞（前LSC）转化为全面白血病（例如急性髓样）的因素 白血病（AML），慢性脊髓细胞白血病（CMML）或严重的骨髓增生性肿瘤 （MPN）。为此，在超过20万的外周血（PB）细胞上进行了广泛的整个外显子组测序 检查了未选择血液学表型的人的160个基因 在白血病中突变。发现的两个最突变的基因是表观遗传调节剂：十个易位 甲基胞嘧啶二加氧酶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患者的基因在非常高的频率下突变。重要的是，流行病学发现 证明患有DM的人比没有DM的人更有可能具有这些突变。然而， 了解我们对DMS警告在MPN中的理解和 白血病。使用TET2功能丧失（TET2 - / - ）的鼠模型的研究表明TET2缺陷型 造血干细胞（HSC）具有绝对的全球5-羟基甲苯蛋白（5-HMC）水平，局部5-- 负责HSC自我更新的基因中的HMC水平。此外，TET2 - / - HSC表现出竞争力 优势（即克隆造血）比正常的HSC相比，但不会发展为AML发育。而且， TET2（TET2 +/-）具有单倍无关的小鼠仅在老化时表现出这些表型的Miller形式 表明TET2充当推定的肿瘤抑制剂。我们发现TET2缺陷小鼠表现出来 对急性炎症和老化的幼稚TET2 - / - 小鼠的持续反应显示一系列的表达升高 编码先天免疫/促炎途径的基因，包括S100A8/9，TLR4，NFκB1 和IL-6。随着DM患者发展慢性感染并增加了S100A8/A9的表达，则 该提议的中心假设是，携带单个遗传病变形式的糖尿病患者 TET2在其HSC中（在没有任何血液学恶性肿瘤的情况下）将更容易受到严重的影响 MPN和/或髓样白血病，部分是过度活跃的促炎细胞因子信号级联反应或前进 进食阳性信号循环，部分诱导高血糖（HG）诱导5-HMC的进一步降低 在LSC前的含量损失TET2的水平，因此模仿了缺乏所有形式的TET的前LSC。确实，通过介绍 TET2突变成糖尿病的鼠模型（ins2akita/+），我们的初步数据表明糖尿病 TET2（INS2AKITA/+; TET2 +/-）的小鼠逐渐发展为致命的AML/严重MPN。重要的是， 用抗炎分子接触到急性炎症挑战的TET2 - / - 小鼠的处理， APX3330，逆转此表型。基于这些初步结果，我们假设该渐进性DM 是将前LSC和/或克隆造血的重大危险因素转化为血红素malignancys 以年龄的方式。