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.

项目总结 生殖系易患恶性血液病(HMS)比以前所认识的更常见，但 个人分布在全国各地，几乎没有当地的专家。美国国立卫生研究院为 Holland和Hickstein博士和RUNX1生殖系患者的GATA2基因突变 刘博士领导下的基因突变。拟议的U01财团将聘请四名外部调查人员，Lucy博士 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)和南希·斯派克(宾夕法尼亚大学)进行互补表演 研究使用了来自NIH临床中心就诊患者的原始样本。炎症增加是 具有生殖系GATA2突变的免疫缺陷个体遭受感染的特征，以及 来自外部调查人员的初步数据表明，生殖系RUNX1突变细胞产生的 炎性分子的水平。U01的研究人员假设炎症源于固有的和 外源性因素导致GATA2突变患者的骨髓衰竭(BMF)，加上克隆性造血(CH) 在这两种综合征中，这经常演变为HMS。U01联盟将使用三个工具来验证这一假设 目的：目标1-通过分析GATA2和RUNX1 VUS对 骨髓造血干/祖细胞(HSPC)和间充质基质细胞(MSCs)。已识别的VUS 在呈现给NIH临床中心的患者中，将使用生长和分化来表征功能 患者来源的HSPC、非造血MSCs的检测，以及以它们为基准的MSC细胞系 野生型和已知的有害或良性变异。目标2-确定炎症机制如何相互作用 生殖系GATA2和RUNX1突变改变HSPC和MSC的生长和分化。我们将确定 RUNX1和GATA2突变的BM细胞过度产生炎性细胞因子/趋化因子 TLR4配体，并测定它们以及内毒素对集落形成、串联复制和 RUNX1和GATA2突变的HSPC和MSCs的分化我们将建立一个临床前模型 炎症诱导的Gata2基因缺陷小鼠的BMF，并确定升高的TLR信号在 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 生殖系突变的造血干细胞。生殖系GATA2-CH患者发生CH的频率更高且年龄更早 和RUNX1-突变与普通人群进行比较。我们将使用异种移植和同基因小鼠模型 为了确定炎症如何导致Gata2基因缺陷小鼠的骨髓衰竭，并促进 具有获得性体细胞突变的生殖系GATA2或RUNX1突变HSPC的生长/存活，提供了 最终演变成白血病的克隆优势。这些研究的结果将被用于设计一种 减少全身炎症、延缓或防止克隆性扩张和发展风险的临床试验 BMF和HMS，从而改善了我们患者的生活。

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