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: 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
• 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

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 造血系统恶性肿瘤（HM）的生殖系易感性比以前认识到的更常见，但 个人分散在全国各地，当地专家很少。NIH提供重点诊所， 根据Holland和Hickstein博士的研究，GATA 2基因突变的患者以及RUNX 1基因突变的患者 在刘博士的领导下进行突变。拟议中的U 01财团将聘请四名校外调查员，露西博士 戈德利（芝加哥大学）、阿努普里亚·阿加瓦尔（俄勒冈州健康与科学大学）、埃默里·布雷斯尼克 （威斯康星大学麦迪逊分校）和南希斯佩克（宾夕法尼亚大学）进行互补 使用NIH临床中心患者的原始样本进行研究。炎症增加是 具有生殖系GATA 2突变的免疫缺陷个体所遭受的感染的特征，和 来自校外研究人员的初步数据表明，生殖系RUNX 1突变细胞产生的 炎症分子的水平。U 01研究者假设炎症来源于内在的， 外源性因素导致GATA 2突变患者骨髓衰竭（BMF），加上克隆性造血（CH） 在这两种综合征中经常演变成HM。U 01联盟将使用三个 目的：目的1-通过分析生殖系GATA 2和RUNX 1 VUS的影响来鉴定哪些生殖系GATA 2和RUNX 1 VUS是有害的。 骨髓造血干细胞和祖细胞（HSPC）和间充质基质细胞（MSC）。识别的VUS 将使用生长和分化功能对NIH临床中心的患者进行功能表征 患者来源的HSPC、非造血MSC和MSC细胞系的测定将它们作为基准， 野生型和已知的有害或良性变体。目的2-确定炎症机制如何相互作用 用种系GATA 2和RUNX 1突变改变HSPC和MSC生长和分化。我们将确定 RUNX 1-和GATA 2-突变BM细胞响应于 TLR 4配体，并确定它们的影响，以及LPS对集落形成，连续重新铺板， RUNX 1和GATA 2突变型HSPC和MSC的分化。我们将建立一个临床前模型， Gata 2缺陷小鼠中炎症诱导的BMF，并确定TLR信号传导升高对炎症诱导的BMF的贡献。 他们的造血缺陷目的3-确定获得性突变和炎症如何促进扩张 生殖系突变的HSC。CH在生殖系GATA 2 - 1患者中发生更频繁，且发生年龄更早。 和RUNX 1-突变相比，一般人群。我们将使用异种移植和同基因小鼠模型 以确定炎症如何驱动Gata 2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GATA 2-或RUNX 1-突变HSPC的生长/存活，提供了一种 克隆优势最终演变成白血病这些研究的结果将用于设计一个 临床试验，以减少全身炎症和延迟或防止克隆扩张和发展的风险 BMF和HM，从而改善我们患者的生活。

项目成果

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。

• DOI: 10.1056/nejmcibr2117528
• 发表时间: 2022
• 期刊: The New England journal of medicine
• 作者: Speck,NancyA