Characterizing stem cell-like B cell subpopulations and dissecting their role in tumorigenesis

表征干细胞样 B 细胞亚群并剖析它们在肿瘤发生中的作用

• 批准号: 10720153
• 负责人: Effie Apostolou
• 金额: $ 40.58万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10720153
• 关键词: Address; Affect; Aftercare; Antigens; B-Cell Activation; B-Cell Lymphomas; B-Lymphocytes; Biological Assay; Cancerous; Cell Reprogramming; Cell Survival; Cells; Chromatin; Dependence; Development; Diagnostic; Disease; Disease Progression; Down-Regulation; Endowment; Enhancers; Epigenetic Process; Gene Expression Profile; Genetic; Genetic Transcription; Genomics; Goals; Hematopoietic Neoplasms; Histone H1; Image; Immuno-Chemotherapy; Immunobiology; Incidence; Lymphoma; Lymphoma cell; Lymphomagenesis; Maintenance; Mature B-Lymphocyte; Mature Lymphocyte; Molecular; Mutation; Nature; Patients; Population; Property; Publishing; Reaction; Regimen; Relapse; Research; Residual state; Resistance; Role; Sampling; Signal Transduction; Solid Neoplasm; Structure of germinal center of lymph node; T-Lymphocyte; TNFSF5 gene; Technology; Testing; Therapeutic; Work; chromatin remodeling; derepression; experience; gain of function; in vivo; induced pluripotent stem cell; induced pluripotent stem cell technology; innovation; large cell Diffuse non-Hodgkin' s lymphoma; leukemia; loss of function; mouse model; multiple omics; novel; pathogen; prevent; progenitor; programs; relapse patients; relapse risk; response; self-renewal; single cell technology; stem; stem cell genes; stem cells; stem-like cell; stemness; synergism; targeted treatment; transcriptional reprogramming; tumor; tumorigenesis; tumorigenic

One third of B-cell lymphoma patients relapse and remain incurable despite effective targeted therapies. Although, the serially relapsing nature of these tumors support the presence of stem- like lymphoma repopulating cells, this notion remains controversial and underexplored. Resistance to this concept arise from the fact that -in contrast to leukemia or other solid tumors that originate from stem-like cells- most lymphomas arise from fully differentiated, mature B cells. However, our preliminary studies provide strong evidence for the existence of rare subpopulations of B-cells undergoing antigen-activation (in response to pathogens) with stem-like molecular features and functional properties in a T-cell dependent manner. Moreover, we found that specific lymphoma-associated mutations further enhance the preexisting stemness program and potential. We, therefore, hypothesize that a subset of mature B cells is transiently endowed with stem-like epigenetic features, which are hijacked by specific lymphoma drivers, and constitute the molecular basis of their increased tumorigenic potential and tumor repopulating capacity. To address this hypothesis, we have built an interdisciplinary team of collaborators with expertise in stem cell reprogramming, epigenetics, immunobiology, single-cell technologies and lymphoma research. We have devised an innovative and bold approach employing multiple cutting-edge single-cell and chromatin technologies, as well as ex vivo and in vivo functional assays that will allow us to (i) determine the key regulators that promote or prevent increased GC B-cell plasticity in normal and cancerous contexts, (ii) decipher the signal and inter- cellular dependencies that enable emergence of a GC stem-like state and key vulnerabilities and (iii) dissect the synergies between common lymphoma drivers with GC stem-like properties, contributing to aggressive disease and relapse. The discovery of B-cell stem-like features and subpopulations will be paradigm-shifting and have a tremendous impact on the way we understand and treat lymphomas, opening new avenues for the development of superior diagnostic and therapeutic strategies.

尽管有有效的靶向治疗，三分之一的 B 细胞淋巴瘤患者仍会复发且无法治愈 疗法。尽管这些肿瘤的连续复发性质支持干细胞的存在 与淋巴瘤细胞再生一样，这一概念仍然存在争议且尚未得到充分探索。 对这一概念的抵制源于以下事实： - 与白血病或其他实体瘤相反 起源于干细胞样细胞——大多数淋巴瘤起源于完全分化的成熟 B 细胞。 然而，我们的初步研究为稀有亚群的存在提供了强有力的证据 B 细胞通过干细胞样分子进行抗原激活（响应病原体） T 细胞依赖性方式的特征和功能特性。此外，我们发现具体 淋巴瘤相关突变进一步增强了先前存在的干性计划 潜在的。因此，我们假设成熟 B 细胞的一个子集被短暂赋予 具有类似茎的表观遗传特征，这些特征被特定的淋巴瘤驱动因素劫持，并且 构成其致瘤潜力和肿瘤增加的分子基础 重新填充能力。为了解决这个假设，我们建立了一个跨学科团队 具有干细胞重编程、表观遗传学、免疫生物学、单细胞专业知识的合作者 技术和淋巴瘤研究。我们设计了一种创新且大胆的方法 采用多种尖端单细胞和染色质技术，以及离体和体内技术 体内功能测定将使我们能够（i）确定促进或预防的关键调节因子 在正常和癌症环境中增加 GC B 细胞可塑性，(ii) 破译信号并相互解释 细胞依赖性使得出现类似 GC 茎的状态和关键漏洞以及 (iii) 剖析常见淋巴瘤驱动因素与 GC 干细胞样特性之间的协同作用， 导致侵袭性疾病和复发。 B细胞干细胞样特征的发现和 亚人群将发生范式转变并对我们的生活方式产生巨大影响 了解和治疗淋巴瘤，为卓越的发展开辟新途径 诊断和治疗策略。