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.

研究综述 对非霍奇金淋巴瘤（NHL）潜在分子机制的理解增加， 侵袭性弥漫性大B细胞淋巴瘤（DLBCL）和惰性边缘区靶向治疗的大门 淋巴瘤（MZL）。基于不同的基因表达谱，DLBCL被分类为B细胞受体 信号传导驱动的活化B细胞样（ABC）亚型和表观遗传学驱动的生发中心B细胞样（GCB） 亚型，但具有广泛不同的结果：ABC-DLBCL是对一线化疗最耐药的亚型。 治疗R-CHOP，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，影响DLBCL的总生存期（OS）。 我们的小组系统地研究了淋巴瘤结局的差异，并确定了非裔美国人（AA） 患者为DLBCL的低风险人群，诊断年龄比其他种族组小10岁。在 监测、流行病学和最终结果（SEER）数据集和其他分析，我们发现AA-DLBCL 患者的5年OS低于非西班牙裔白人（38% vs 46）。Koff博士进行了 首次描述AA-DLBCL患者的遗传改变，并证明了不同的突变 在离散的祖先群体中产生的DLBCL模式。虽然一些最常见的基因突变 在AA-DLBCL与染色质和表观遗传学有关，很少有研究调查患者的种族差异 攻击性ABC DLBCL和惰性MZL。在一项对无痛性心律失常患者进行的大规模、基于人群的分析中， 在美国NHL中，美国血液学会提供的数据报告了种族和民族 在过去的二十年里，少数民族的死亡率上升，AA是死亡率第二高的群体。的机制 确定这种种族不平等是未知的，但可能在于特定的突变谱， 与淋巴结肿瘤微环境（Ly-TME）传递的复杂生存信号。调查 可能导致淋巴瘤中种族差异的分子因素受到以下因素的限制， AA患者的代表性，即使在非常大的淋巴瘤生物储存库中。R 01的长期目标是 通过Ly-TME和TME之间的复杂相互作用，了解淋巴瘤结局的种族差异。 AA患者样品中的DLBCL和MZL细胞，在可调水凝胶中重现AA-DLBCL和AA-MZL Ly-TME 平台，并确定Ly-TME对肿瘤存活、信号传导和对BCR通路抑制剂的反应的作用。 R 01是创新的，因为它调查了种族差异AA-Ly-TME的潜在机制，并开发了 AA-DLBCL类器官。拟议的工作是重要的，因为它将研究AA-Ly-TME与 白色患者的情况，并确定其对BCR信号传导和BTKi的影响。