Programmed necrosis regulation of leukemic transformation

白血病转化的程序性坏死调控

• 批准号: 10477217
• 负责人: Sandra S Zinkel
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10477217
• 关键词: Abnormal Cell; Acute Myelocytic Leukemia; Anemia; Automobile Driving; Benign; Biology; Blood; Blood Cells; Bone Marrow; Bone marrow failure; Cardiovascular Diseases; Cell Death; Cell Death Signaling Process; Cells; Chronic; Clinical; Clonal Evolution; Clonal Expansion; Clone Cells; Crohn' s disease; Data; Development; Disease; Dysmyelopoietic Syndromes; Early Intervention; Electronic Health Record; Etanercept; Evolution; Frequencies; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genetic study; Genomics; Growth; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Human; Humira; Immune; Impairment; Individual; Inflammation; Inflammatory; Inflammatory Response; Interruption; Intervention; Knowledge; Malignant - descriptor; Malignant Neoplasms; Methodology; Molecular; Mutate; Mutation; Necrosis; Pathogenesis; Pathway interactions; Patients; Pharmacology; Phosphotransferases; Population; Predisposing Factor; Process; Prognosis; RIPK1 gene; Regulation; Resources; Rheumatoid Arthritis; Risk; Risk Factors; Sampling; Signal Pathway; Signal Transduction; TNF gene; Therapeutic; Therapeutic Uses; Time; cytokine; disorder risk; driver mutation; expression cloning; genetic analysis; genetic architecture; genetic variant; inhibitor; interdisciplinary approach; leukemia; leukemic transformation; modifiable risk; mouse model; myelodysplastic anemia; next generation sequencing; novel; overexpression; prevent; scaffold; stem cell expansion; tool; translational medicine; whole genome

Cancer arises from the acquisition of multiple genetic alterations, often preceded by expansion of a clonal cell population with a growth or survival advantage. Clonally restricted blood cell development (hematopoiesis) is a common feature in benign and malignant blood disorders. Whole genome genetic studies have identified driver mutations associated with clonal hematopoietic diseases such as myelodysplastic syndrome (MDS), and acute myelogenous leukemia (AML) [1-4]. Subsequent studies showed that normal individuals may also harbor clonal hematopoiesis that is associated with increased risk of hematopoietic as cardiovascular disease (CVD) [5, 6]. Clonal hematopoiesis develops into MDS or AML at a low frequency (~1%), increasing to 80% once low blood counts develop. AML and MDS prognoses are poor, with limited treatment options. Next generation sequencing (NGS) of genes mutated in clonal hematopoiesis is clinically available but does not predict who will progress to from clonal hematopoiesis to MDS or AML. A key question in the field is: What are the factors that predispose to progression from clonal hematopoiesis to MDS or AML? The overarching hypothesis is that bone marrow inflammation triggers programmed necrosis in hematopoietic stem and progenitor cells. This in turn sets up a feed-forward inflammatory response that can drive clonal expansion and evolution to MDS and AML from clonal hematopoiesis. Interrupting cell death signaling or altering inflammatory signaling has the potential to prevent disease evolution for therapeutic benefit. Aim 1: Compare and contrast the impact of chronic inflammation on inflammatory and cell death signaling in mouse models of mutations found in clonal hematopoiesis and mouse models of unrestrained necrosis to determine the molecular decision drivers and how these drivers alter clonal expansion, differentiation, and clonal evolution (acquisition of additional mutations). Aim 2. Determine whether pharmacologic inhibition (GSK RIPK1 inhibitor tool compound) or genetic inactivation of either Rip1 kinase or RipK1 scaffolding function will prevent clonal expansion and clonal evolution. Determine whether inhibiting cytokines (Enbrel, Humira) will prevent clonal expansion and clonal evolution. Aim 3: Determine whether genetically determined changes in expression of genes that drive necroptosis or innate immune inflammation and their regulatory genetic variants (SNPs), A) associate significantly with risk of human anemia, MDS, AML B) cooperate with mutations associated with CHIP (TET2, ASXL1) in the risk of human anemia, MDS and AML. This proposal will fill an important gap in our knowledge of the biology of clonal hematopoiesis, MDS and AML in that it will identify gene pathways that underlie a germline genetic predisposition to progression to symptomatic disease. These studies have the potential to fundamentally change the approach to MDS as well as clonal hematopoiesis by identifying patients at risk of progression to MDS and identifying early intervention strategies. Incorporation of electronic health records into our methodology has the potential to accelerate translational medicine, bridging the gap between clinical information and functional data.

癌症是由于获得多种遗传改变而引起的，通常是在克隆细胞的扩张之前 人口具有增长或生存优势。克隆受限的血细胞发育（造血）是 良性和恶性血液疾病的共同特征。整个基因组遗传研究已经鉴定出驱动因素 与克隆造血疾病有关的突变，例如骨髓增生综合征（MDS）和急性 髓性白血病（AML）[1-4]。随后的研究表明，正常个体也可能携带克隆 造血与增加造血的风险作为心血管疾病（CVD）[5，6]。 克隆造血症以低频率（约1％）形成MDS或AML，一旦血液低血液 计数发展。 AML和MD的预后很差，治疗方案有限。下一代测序 克隆造血中突变的基因的（NG）在临床上可用，但不能预测谁将发展为 从克隆造血到MDS或AML。该领域的一个关键问题是：易感性的因素是什么 从克隆造血到MDS或AML的发展？ 总体假设是骨髓炎症触发了编程的坏死 造血干和祖细胞。反过来，这设置了前馈发炎 可以驱动克隆扩张和进化对MD和AML的响应 造血。中断细胞死亡信号传导或改变炎症信号传导具有 预防治疗益处的疾病进化的潜力。 目标1：比较和对比慢性炎症对炎症和细胞死亡信号传导的影响 在克隆造血和不受约束坏死的小鼠模型中发现的突变的小鼠模型 确定分子决策驱动因素以及这些驱动因素如何改变克隆扩张，分化和 克隆进化（获得其他突变）。 目标2。确定药理学抑制（GSK RIPK1抑制剂工具化合物）还是遗传 RIP1激酶或RIPK1脚手架功能的失活将防止克隆膨胀和克隆 进化。确定抑制细胞因子（Enbrel，Humira）是否会防止克隆膨胀和克隆 进化。 目标3：确定遗传确定的驱动坏死性基因表达的变化还是 先天免疫炎症及其调节性遗传变异（SNP），a）与风险显着相关 人类贫血，MDS，AML b）与芯片（TET2，ASXL1）相关的突变合作 人类贫血，MD和AML。 该建议将填补我们对克隆造血，MD和AML的生物学知识的重要空白 因为它将确定基因途径是生殖线遗传易感性的基因途径 有症状的疾病。这些研究有可能从根本上改变MD的方法以及 克隆造血作用，通过识别有进展为MD的患者并确定早期干预 策略。将电子健康记录纳入我们的方法论有可能加速 翻译医学，弥合临床信息和功能数据之间的差距。