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

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， 治疗虽然，这些肿瘤的连续复发性质支持干细胞的存在， 像淋巴瘤再生细胞一样，这一概念仍然存在争议和探索不足。 对这一概念的抵抗来自于以下事实-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细胞经历干细胞样分子的抗原活化（响应病原体） 特征和功能性质的T细胞依赖性的方式。此外，我们还发现， 淋巴瘤相关突变进一步增强了先前存在的干性程序， 潜力因此，我们假设成熟B细胞的一个亚群被瞬时赋予了 具有干细胞样表观遗传特征，被特定的淋巴瘤驱动程序劫持， 构成了它们增加的致瘤潜力和肿瘤的分子基础。 再生能力。为了解决这个假设，我们建立了一个跨学科的团队， 在干细胞重编程、表观遗传学、免疫生物学、单细胞 技术和淋巴瘤研究。我们设计了一个创新和大胆的方法 采用多种尖端的单细胞和染色质技术，以及体外和体内 体内功能测定将使我们能够（i）确定促进或阻止 在正常和癌性环境中增加GC B细胞可塑性，（ii）破译信号和内部 细胞依赖性，使得出现类似GC stem的状态和关键漏洞， (iii)剖析常见的淋巴瘤驱动因素与GC茎样特性之间的协同作用， 导致疾病的侵袭和复发。B细胞干细胞样特征的发现， 亚群将是范式转变，并对我们的方式产生巨大影响， 了解和治疗淋巴瘤，开辟新的途径，为发展上级 诊断和治疗策略。

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.