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

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.