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.

癌症是由多种基因改变引起的，通常先于克隆细胞的扩增 具有增长或生存优势的人口。克隆限制性血细胞发育（造血）是一种 良性和恶性血液疾病的共同特征。全基因组遗传学研究已确定驱动因素 与克隆性造血疾病相关的突变，例如骨髓增生异常综合征（MDS）和急性 骨髓性白血病（AML）[1-4]。随后的研究表明，正常个体也可能携带克隆病毒 造血功能与心血管疾病 (CVD) 等造血功能的风险增加有关 [5, 6]。 克隆性造血发展为 MDS 或 AML 的频率较低（~1%），一旦低血率则增加至 80% 计数发展。 AML 和 MDS 预后较差，治疗选择有限。下一代测序 克隆造血中突变的基因（NGS）在临床上可用，但不能预测谁将进展为 从克隆性造血到 MDS 或 AML。该领域的一个关键问题是：哪些因素会导致 从克隆性造血进展到 MDS 或 AML？ 最重要的假设是骨髓炎症会引发程序性坏死 造血干细胞和祖细胞。这反过来又建立了前馈炎症 可以驱动克隆扩展和从克隆向 MDS 和 AML 进化的反应 造血作用。中断细胞死亡信号或改变炎症信号具有 预防疾病演变以获得治疗益处的潜力。 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 克隆造血中发现突变的小鼠模型和不受限制的坏死的小鼠模型 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增、分化和 克隆进化（获得额外突变）。 目标 2. 确定药物抑制（GSK RIPK1 抑制剂工具化合物）还是遗传抑制 Rip1 激酶或 RipK1 支架功能失活将阻止克隆扩增和克隆 进化。确定抑制细胞因子（Enbrel、Humira）是否会阻止克隆扩增和克隆 进化。 目标 3：确定驱动坏死性凋亡的基因表达变化是否是由基因决定的 先天性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 CHIP 相关突变（TET2、ASXL1）合作，导致以下风险： 人类贫血、MDS 和 AML。 该提案将填补我们在克隆造血、MDS 和 AML 生物学知识方面的重要空白 因为它将识别出种系遗传倾向下的基因途径，以发展为 有症状的疾病。这些研究有可能从根本上改变 MDS 的治疗方法以及 通过识别有进展为 MDS 风险的患者并确定早期干预来进行克隆造血 策略。将电子健康记录纳入我们的方法有可能加速 转化医学，弥合临床信息和功能数据之间的差距。