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.

研究概要 加深对非霍奇金淋巴瘤 (NHL) 分子机制的了解 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）。根据不同的基因表达谱，DLBCL 分为 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 细胞样 (GCB) 不同亚型，但结果差异很大：ABC-DLBCL 是一线化疗耐药性最强的亚型 R-CHOP 疗法，40% 的患者没有反应或复发。 Co-I Jean Koff 博士的合作 研究表明，基因改变与临床因素相互作用，影响 DLBCL 的总生存期 (OS)。 我们的小组系统地检查了淋巴瘤结果的差异，并确定了非裔美国人 (AA) 患者属于DLBCL的低危人群，诊断年龄比其他种族群体年轻10岁。在 通过监测、流行病学和最终结果 (SEER) 数据集和其他分析，我们发现 AA-DLBCL 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 首次对 AA-DLBCL 患者的基因改变进行表征，并证明了明显的突变 DLBCL 的模式出现在离散的祖先群体中。虽然一些最常见的基因突变 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 具有侵袭性 ABC DLBCL 和惰性 MZL。在一项针对惰性患者的大规模、基于人群的分析中 美国血液学会公布的数据显示，美国 NHL 的种族和民族生存率较低 过去二十年中，少数族裔死亡率最高，AA 族是死亡率第二高的群体。的机制 决定这种种族不平等的因素尚不清楚，但可能存在于协同作用的特定突变谱中 淋巴结肿瘤微环境（Ly-TME）传递复杂的生存信号。调查 可能导致淋巴瘤种族差异的分子因素受到以下因素的限制： AA 患者的代表性，即使是在非常大的淋巴瘤生物存储库中。 R01的长期目标是 通过 Ly-TME 和 Ly-TME 之间复杂的相互作用来了解淋巴瘤结果的种族差异 AA 患者样本中的 DLBCL 和 MZL 细胞，在可调谐水凝胶中重现 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 途径抑制剂的反应的作用。 R01 具有创新性，因为它研究了种族差异 AA-Ly-TME 的潜在机制并开发了 AA-DLBCL 类器官。拟议的工作意义重大，因为它将研究 AA-Ly-TME 与 并确定其对 BCR 信号传导和 BTKi 的影响。