Identification of driver proteins for accelerating immune recovery post chemotherapy

Following chemotherapy, the immune system takes a long time to rebuild - putting the patient at high risk for life threatening infections and reduced ability to fight against cancer. Hence, to improve survival rate of cancer patients, it is crucial to accelerate their immune reconstitution. B lymphopoiesis is a linear process originating from bone marrow (BM) hematopoietic stem and progenitor cells (HSPC) and which is regulated by mesenchymal stromal cell (MSC) niches. By analyzing scRNA-seq data of healthy human BM aspirates, we generated a high dimensional B cell developmental trajectory. Cell communication is required for the proper functioning of tissues and relies on interactions between receptors and their ligands. Accordingly, we utilized known ligand-receptor pairings to identify stromal cell-derived ligands that interact with B-cell subpopulations. To further narrow down the list of drivers and focus on factors critical to post-chemotherapy reconstitution, we analyzed scRNA-seq data from acute myeloid leukemia (AML) patients following treatment, and observed an accumulation of developmental intermediates at the ProB stage. Accordingly, we reduced our target list to drivers that interact with differentiation receptors at the HSC/CLP stage and proliferation receptors at the ProB stage. Finally, we established an in-vitro system, by co-culturing MSC with human CD34+ HSPC and cytokines, to mimic the development of B cells and further investigate the defined drivers. In summary, we developed a method for systems-level analysis of B lymphopoiesis in health and recovery post chemotherapy, which may enable us to discover ways to intelligently boost immune system regeneration in AML patients.