Hydrogel-based Organoids of African-American Lymphomas to Study B Cell Receptor Pathway Inhibitors

基于水凝胶的非裔美国人淋巴瘤类器官用于研究 B 细胞受体通路抑制剂

• 批准号: 10539628
• 负责人: JEAN L KOFF
• 金额: $ 56.36万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10539628
• 关键词: 1-Phosphatidylinositol 3-Kinase; 10 year old; Address; African American; African ancestry; Agammaglobulinaemia tyrosine kinase; American Society of Hematology; Antigens; B-Cell Activation; B-Cell Antigen Receptor; B-Cell Lymphomas; B-Lymphocytes; Biophysics; Cell Survival; Cells; Chemoresistance; Chromatin; Clinical; Complex; Cues; DNA Sequence Alteration; Data; Data Set; Databases; Diagnosis; Engineering; Epigenetic Process; European; Exhibits; Extracellular Matrix; Feedback; Gene Expression; Goals; Hydrogels; Immune; In complete remission; Indolent; Inferior; Integrins; Investigation; Ligands; Lymphoid; Lymphoma; Lymphoma cell; Maintenance; Manuscripts; Mediating; Molecular; Mutation; Non-Hodgkin' s Lymphoma; Not Hispanic or Latino; Oncogenic; Organoids; Outcome; Pathogenesis; Pathway interactions; Patients; Pattern; Population; Primary Neoplasm; Race; Receptor Activation; Receptor Signaling; Refractory; Relapse; Reporting; Research; Research Personnel; Resistance; Risk; Role; SEER Program; Sampling; Sgk protein; Signal Pathway; Signal Transduction; Structure of germinal center of lymph node; T-Lymphocyte; Toll-like receptors; Translational Research; Tyrosine Kinase Inhibitor; Work; Xenograft procedure; base; biobank; cell stroma; cohort; epidemiology study; ethnic minority; exome sequencing; experience; improved outcome; inhibitor; innovation; large cell Diffuse non-Hodgkin' s lymphoma; lymph nodes; mortality; neoplastic cell; partial response; population based; racial determinant; racial difference; racial disparity; racial minority; response; targeted treatment; transcriptome sequencing; tumor; tumor growth; tumor microenvironment

RESEARCH SUMMARY Increased understanding of the molecular mechanisms underlying non-Hodgkin's lymphoma (NHL) has opened the door for targeted therapy in aggressive diffuse large B-cell lymphoma (DLBCL) and indolent marginal zone lymphomas (MZLs). Based on distinct gene expression profiles, DLBCLs are classified into B cell receptor signaling-driven activated B cell-like (ABC) subtypes and epigenetics-driven germinal center B cell-like (GCB) subtypes but have widely divergent outcomes: ABC-DLBCL is the most chemo-resistant subtype to the frontline therapy R-CHOP, with 40% of patients experiencing no response or relapse. Co-I Dr. Jean Koff's collaborative research showed that genetic alterations interact with clinical factors to impact overall survival (OS) in DLBCL. Our group has systematically examined disparities in lymphoma outcomes and identified African-American (AA) patients as a poor-risk population in DLBCL, with diagnosis age 10 years younger than other racial groups. In the Surveillance, Epidemiology and End Results (SEER) dataset and other analyses, we found that AA-DLBCL patients experienced inferior 5-year OS compared to non-Hispanic whites (38% vs 46). Dr. Koff performed the first-ever characterization of genetic alterations among AA-DLBCL patients and demonstrated distinct mutation patterns across DLBCL arising in discrete ancestry groups. While some of the most frequent genetic mutations in AA-DLBCL are related to chromatin and epigenetics, few studies have investigated racial disparities in patients with aggressive ABC DLBCLs and indolent MZLs. In a large, population-based analysis of patients with indolent NHL in the US, data presented at American Society for Hematology reported inferior survival in racial and ethnic minorities over the past two decades, with AAs among the 2nd highest mortality group. The mechanisms that determine this racial inequality are unknown, but may lie in the particular spectrum of mutations that act in concert with intricate survival signals imparted by the lymph node tumor microenvironment (Ly-TME). Investigations into the molecular factors that may contribute to racial disparities in lymphoma have been limited by the under- representation of AA patients, even in very large lymphoma biorepositories. The long-term goal of this R01 is to understand the racial disparities in lymphoma outcomes through complex interactions between Ly-TME and DLBCL and MZL cells in AA patient samples, recapitulate AA-DLBCL and AA-MZL Ly-TME in a tunable hydrogel platform, and determine the role of Ly-TME on tumor survival, signaling, and response to BCR pathway inhibitors. The R01 is innovative because it investigates mechanisms underlying racial disparity AA-Ly-TME and develops AA-DLBCL organoids. The proposed work is significant because it will examine how AA-Ly-TME differs from that of white patients and determine its impact on BCR signaling and BTKi.

研究摘要 对非霍奇金淋巴瘤（NHL）的分子机制的了解增加了 攻击性弥漫性大型B细胞淋巴瘤（DLBCL）和惰性边缘区域的靶向治疗门 淋巴瘤（MZL）。基于不同的基因表达谱，将DLBCL分类为B细胞受体 信号驱动的活化B细胞样（ABC）亚型和表观遗传学驱动的生发中心B细胞（GCB） 亚型但具有广泛分歧的结果：ABC-DLBCL是前线最具化学性的亚型 治疗R-CHOP，有40％的患者没有反应或复发。 Co-I Jean Koff博士的合作 研究表明，遗传改变与临床因素相互作用，以影响DLBCL的总生存率（OS）。 我们的小组系统地检查了淋巴瘤结局的差异，并确定了非裔美国人（AA） 患者的DLBCL风险较差，诊断比其他种族群体年轻10岁。在 监视，流行病学和最终结果（SEER）数据集和其他分析，我们发现AA-DLBCL 与非西班牙裔白人相比，患者的5年OS较差（38％vs 46）。科夫博士执行了 有史以来对AA-DLBCL患者遗传改变的首先表征，并显示出明显的突变 DLBCL的模式在离散的祖先组中产生。虽然一些最常见的基因突变 在AA-DLBCL中，与染色质和表观遗传学有关，很少研究患者的种族差异 具有积极的ABC DLBCL和懒惰的MZL。在大型，基于人群的分析中 NHL在美国，美国血液学学会提出的数据报道了种族和种族的生存率较低 在过去的二十年中，少数民族在第二高死亡率组中有AAS。这些机制 确定这种种族不平等是未知的，但可能在于特定的突变范围 淋巴结肿瘤微环境（LY-TME）赋予了复杂的生存信号。调查 可能导致淋巴瘤种族差异的分子因素受到限制 AA患者的代表，即使在非常大的淋巴瘤生物疗法中也是如此。此R01的长期目标是 通过LY-TME和 AA患者样品中的DLBCL和MZL细胞，在可调水凝胶中概括AA-DLBCL和AA-MZL LY-TME 平台，并确定LY-TME对BCR途径抑制剂的肿瘤存活，信号传导和反应的作用。 R01具有创新性，因为它研究了种族差异的基础机制AA-Ly-TME并发展 AA-DLBCL器官。拟议的工作很重要，因为它将检查AA-Ly-TME与 白人患者的影响并确定其对BCR信号和BTKI的影响。