The role of inflammation in driving leukemogenesis in germline predisposition syndromes

炎症在驱动种系易感综合征中白血病发生中的作用

• 批准号: 10394048
• 负责人: Anupriya Agarwal
• 金额: $ 70.79万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10394048
• 关键词: Acute T Cell Leukemia; Adolescent; Age; Automobile Driving; B lymphoid malignancy; B-Lymphocytes; Benchmarking; Benign; Biological Assay; Biological Markers; Blood Platelets; Bone marrow failure; Cell Line; Cells; Characteristics; Chicago; Clinic; Clinical Trials; Clinical assessments; Clonal Expansion; Collection; Country; Data; Defect; Dendritic Cells; Development; Differentiation and Growth; Disease; Drug usage; Dysmyelopoietic Syndromes; Extramural Activities; Family; Gene Mutation; General Population; Growth; Health Sciences; Hematopoiesis; Hematopoietic; Hematopoietic Neoplasms; Hematopoietic stem cells; Immune; In Vitro; Individual; Infection; Inflammation; Inflammatory; Inherited; Laboratories; Lead; Ligands; Malignant Neoplasms; Monosomy 7; Mus; Mutation; Mycoses; Myeloproliferative disease; Natural Killer Cells; Oregon; Pathogenicity; Pathway interactions; Patients; Pennsylvania; Pre-Clinical Model; Predisposition; RUNX1 gene; Research Personnel; Risk; Role; Sampling; Signal Transduction; Somatic Mutation; Source; Syndrome; TLR4 gene; Testing; Translational Research; United States National Institutes of Health; Universities; Variant; Viral; Wisconsin; Work; Xenograft procedure; acute infection; chemokine; chronic infection; clinical center; cytokine; design; driver mutation; high risk; improved; inflammatory milieu; innovation; interest; leukemia; leukemogenesis; mesenchymal stromal cell; monocyte; mouse model; mutant; mutation carrier; non-tuberculosis mycobacteria; novel strategies; prevent; programs; research clinical testing; response; stem cell growth; systemic inflammatory response; transcription factor; variant of unknown significance

PROJECT SUMMARY Germline predisposition to hematopoietic malignancies (HMs) is more common than previously appreciated, but individuals are spread throughout the country, with few local experts. The NIH provides focused clinics for patients with germline GATA2 mutations under Drs. Holland and Hickstein and for those with germline RUNX1 mutations under Dr. Liu. The proposed U01 consortium will engage four extramural investigators, Drs. Lucy Godley (The University of Chicago), Anupriya Agarwal (Oregon Health & Science University), Emery Bresnick (University of Wisconsin-Madison), and Nancy Speck (University of Pennsylvania) to perform complementary studies using primary samples from patients seen at the NIH Clinical Center. Increased inflammation is characteristic of the infections suffered by immunodeficient individuals with germline GATA2 mutations, and preliminary data from the extramural investigators suggest that germline RUNX1-mutant cells produce increased levels of inflammatory molecules. The U01 investigators hypothesize that inflammation derived from intrinsic and extrinsic sources drives bone marrow failure (BMF) in GATA2-mutant patients, plus clonal hematopoiesis (CH) that frequently evolves into HMs in both syndromes. The U01 consortium will test this hypothesis using three Aims: Aim 1- Identify which germline GATA2 and RUNX1 VUSs are deleterious by analyzing their influences on BM hematopoietic stem and progenitor cells (HSPCs) and mesenchymal stromal cells (MSCs). VUSs identified in patients presenting to the NIH Clinical Center will be characterized functionally using growth and differentiation assays of patient-derived HSPCs, non-hematopoietic MSCs, and an MSC cell line benchmarking them against wild-type and known deleterious or benign variants. Aim 2- Establish how inflammatory mechanisms interface with germline GATA2 and RUNX1 mutations to alter HSPC and MSC growth and differentiation. We will identify the inflammatory cytokines/chemokines overproduced by RUNX1- and GATA2-mutant BM cells in response to TLR4 ligands and determine their impact as well as that of LPS on colony formation, serial-replating, and differentiation of RUNX1- and GATA2-mutant HSPCs and MSCs. We will establish a pre-clinical model of inflammation-induced BMF in Gata2-deficient mice and determine the contribution of elevated TLR signaling to their hematopoietic defects. Aim 3- Determine how acquired mutations and inflammation promote the expansion of germline-mutant HSCs. CH occurs more frequently and at an earlier age in patients with germline GATA2- and RUNX1-mutations compared to the general population. We will use xenograft and syngeneic mouse models to determine how inflammation drives bone marrow failure in Gata2-deficient mice and facilitates the growth/survival of germline GATA2- or RUNX1-mutant HSPCs with acquired somatic mutations, providing a clonal advantage that ultimately evolves into leukemia. The results of these studies will be used to design a clinical trial to decrease systemic inflammation and delay or prevent clonal expansion and risk of developing BMF and HMs, thus improving the lives of our patients.

项目摘要 种系对造血恶性肿瘤（HMS）的易感性比以前所欣赏的更为普遍，但 个人分布在全国各地，很少有当地专家。 NIH为专注的诊所提供 DRS下的种系GATA2突变的患者。荷兰和希克斯坦，对于那些具有生殖线runx1的人 刘博士的突变。拟议的U01财团将与四名壁外研究人员聘请。露西 戈德利（芝加哥大学），Anupriya Agarwal（俄勒冈州健康与科学大学），Emery Bresnick （威斯康星大学 - 麦迪逊分校）和南希·斯派克（Nancy Speck）（宾夕法尼亚大学） 研究使用NIH临床中心患者的主要样本的研究。炎症增加是 免疫缺陷的个体患有生殖线GATA2突变的感染的特征， 来自壁外研究人员的初步数据表明，生殖线runx1突变细胞产生增加 炎症分子的水平。 U01研究人员假设源自内在和 外部来源驱动GATA2突变患者的骨髓衰竭（BMF），以及克隆造血（CH） 这经常演变成两个综合征中的HM。 U01联盟将使用三个 目的：目标1-通过分析其影响，确定哪种种系GATA2和Runx1 vuss有害 BM造血干细胞（HSPC）和间充质基质细胞（MSC）。努力被确定 在出现在NIH临床中心的患者中，将使用生长和分化在功能上表征 对患者衍生的HSPC，非脊髓质MSC和MSC细胞系进行测定，将其基准测试 野生型和已知的有害或良性变体。目标2-确定炎症机制如何接口 种系GATA2和RUNX1突变以改变HSPC以及MSC的生长和分化。我们将确定 RUNX1-和GATA2突变的BM细胞过多生产的炎性细胞因子/趋化因子响应于 TLR4配体并确定其影响以及LP对菌落形成，串行复发和 RUNX1-和GATA2突变的HSPC和MSC的区分。我们将建立一个临床前模型 炎症引起的GATA2缺陷小鼠中的BMF，并确定升高TLR信号的贡献 他们的造血缺陷。目标3-确定获得的突变和炎症如何促进扩张 种系突变的HSC。 CH发生的频率更高，在生殖线GATA2-患者的年龄更早发生 与普通人群相比，Runx1-Mutation。我们将使用异种移植物和合成小鼠模型 确定炎症如何驱动GATA2缺陷小鼠的骨髓衰竭并促进 具有获得的体细胞突变的种系GATA2-或RUNX1突变的生长/生存率，提供了一种 克隆优势最终发展为白血病。这些研究的结果将用于设计 临床试验以减少全身性炎症，延迟或防止克隆扩张和发展的风险 BMF和HMS，从而改善了我们患者的生活。