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.

三分之一的B细胞淋巴瘤患者复发，尽管有有效的靶向治疗，但仍无法治愈 治疗。虽然，这些肿瘤的连续复发性质支持干细胞的存在- 就像淋巴瘤重新滋生细胞一样，这一概念仍然存在争议，而且没有得到充分的研究。 与白血病或其他实体肿瘤形成对比的是，对这一概念的抵抗力 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。 用干细胞样分子进行抗原激活(对病原体的反应)的B细胞 功能特性和功能特性以T细胞依赖的方式。此外，我们发现具体的 淋巴瘤相关突变进一步加强了先前存在的干细胞计划和 潜力。因此，我们假设成熟的B细胞的一个子集是暂时的 具有类似干细胞的表观遗传特征，被特定的淋巴瘤驱动因素劫持，以及 构成了它们增强致癌潜能和肿瘤的分子基础 重新填充容量。为了解决这一假设，我们建立了一个跨学科的团队 在干细胞重新编程、表观遗传学、免疫生物学、单细胞领域拥有专业知识的合作者 技术和淋巴瘤研究。我们设计了一种创新和大胆的方法 采用多种尖端的单细胞和染色质技术，以及体外和体内 体内功能分析，将使我们能够(I)确定促进或防止 在正常和癌症情况下，GC B细胞可塑性增加，(Ii)破译信号和相互作用 导致出现GC干状状态和关键漏洞的细胞依赖关系 (Iii)剖析具有GC干细胞样特性的常见淋巴瘤驱动因素之间的协同作用， 导致侵袭性疾病和复发。B细胞干细胞样特征的发现和 子群体将改变模式，并对我们的方式产生巨大影响 认识和治疗淋巴瘤，为SUBERVER的发展开辟新途径 诊断和治疗策略。