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

基本信息

批准号：
10908063
负责人：
Anupriya Agarwal
金额：
$ 68.76万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10908063
关键词：
Acceleration 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 Differentiation process Cell Line Cells Characteristics Chicago Classification 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 Hematopoiesis Hematopoietic Hematopoietic Neoplasms Hematopoietic stem cells Immune Immunologic Deficiency Syndromes In Vitro Individual Infection Inflammation Inflammatory Inflammatory Response Inherited Laboratories 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 Science 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 cell growth chemokine chronic infection clinical center cytokine derepression design driver mutation hematopoietic stem cell expansion 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

项目摘要

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.

项目概要造血系统恶性肿瘤 (HMs) 的种系易感性比以前认为的更为常见，但是人员遍布全国各地，当地专家很少。 NIH 为以下人群提供重点诊所： Drs 治疗下患有种系 GATA2 突变的患者。 Holland 和 Hickstein 以及对于那些具有种系 RUNX1 的人刘博士的突变。拟议的 U01 联盟将聘请四名校外调查员，Drs.露西 Godley（芝加哥大学）、Anupriya Agarwal（俄勒冈健康与科学大学）、Emery Bresnick （威斯康星大学麦迪逊分校）和 Nancy Speck（宾夕法尼亚大学）进行互补使用来自 NIH 临床中心患者的原始样本进行的研究。炎症加剧是具有种系 GATA2 突变的免疫缺陷个体所遭受的感染的特征，以及来自外部研究人员的初步数据表明，种系 RUNX1 突变细胞产生的炎症分子的水平。 U01 研究人员假设炎症源自内在和外在因素导致 GATA2 突变患者骨髓衰竭 (BMF) 以及克隆造血 (CH) 在这两种综合征中经常会演变成 HM。 U01 联盟将使用三种方法来检验这一假设目标：目标 1 - 通过分析其对生殖系 GATA2 和 RUNX1 VUS 的影响，确定哪些种系 GATA2 和 RUNX1 VUS 是有害的。 BM 造血干细胞和祖细胞 (HSPC) 以及间充质基质细胞 (MSC)。已识别的 VUS 将使用生长和分化对就诊于 NIH 临床中心的患者进行功能表征对患者来源的 HSPC、非造血 MSC 和 MSC 细胞系进行测定，并对其进行基准测试野生型和已知的有害或良性变体。目标 2 - 确定炎症机制如何相互作用种系 GATA2 和 RUNX1 突变可改变 HSPC 和 MSC 的生长和分化。我们将确定 RUNX1 和 GATA2 突变型 BM 细胞过度产生炎症细胞因子/趋化因子 TLR4 配体并确定它们以及 LPS 对集落形成、连续重新铺板和 RUNX1 和 GATA2 突变 HSPC 和 MSC 的分化。我们将建立一个临床前模型 Gata2 缺陷小鼠中炎症诱导的 BMF 并确定 TLR 信号传导升高对他们的造血缺陷。目标 3 - 确定获得性突变和炎症如何促进扩张种系突变的 HSC。种系 GATA2- 患者的 CH 发生频率更高且年龄更早和 RUNX1 突变与一般人群相比。我们将使用异种移植和同基因小鼠模型确定炎症如何导致 Gata2 缺陷小鼠的骨髓衰竭并促进具有获得性体细胞突变的种系 GATA2 或 RUNX1 突变 HSPC 的生长/存活，提供最终演变成白血病的克隆优势。这些研究的结果将用于设计减少全身炎症并延迟或预防克隆扩张和发展风险的临床试验 BMF 和 HMs，从而改善我们患者的生活。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Hematopoietic Cell Autonomous Disruption of Hematopoiesis in a Germline Loss-of-function Mouse Model of RUNX1-FPD.

DOI：
10.1097/hs9.0000000000000824
发表时间：
2023-02
期刊：
HEMASPHERE
影响因子：
6.6
作者：
Ernst, Martijn P. T.;Pronk, Eline;van Dijk, Claire;van Strien, Paulina M. H.;van Tienhoven, Tim V. D.;Wevers, Michiel J. W.;Sanders, Mathijs A.;Bindels, Eric M. J.;Speck, Nancy A.;Raaijmakers, Marc H. G. P.
通讯作者：
Raaijmakers, Marc H. G. P.

A Pernicious Cycle Affecting Premalignant Stem Cells.

影响癌前干细胞的恶性循环。