Signal-Transducing Adaptor Protein-2 Governs Recovery of B Lineage Lymphocytes during hematopoietic stress.

Signal-transducing adaptor protein-2 (STAP-2) was discovered as a c-fms/M-CSFR interacting protein and subsequently found to function as an adaptor of signaling or transcription factors. These include STAT5, MyD88 and IB kinase (IKK) in macrophages, mast cells and T cells. There is additional information about roles in several types of malignant diseases including chronic myeloid leukemia, but none concerning B lineage lymphocytes. We have now exploited gene targeted and transgenic mice to address this issue and learned that it is not required under normal, steady-state conditions. However, recovery of B cells following transplantation was augmented in the absence of STAP-2. This appeared to be restricted to cells of this lineage and myeloid rebound was unremarkable. Furthermore, all hematological parameters were normal once recovery from transplantation was complete. Overexpression of STAP-2 specifically in lymphoid cells resulted in reduced numbers of late-stage B progenitors within bone marrow. While numbers of mature peripheral B and T cells were unaffected, recovery from sub-lethal irradiation or transplantation was dramatically reduced. LPS normally suppresses B precursor expansion in response to interleukin 7, but STAP-2 deficiency made them more resistant. Preliminary RNA-Seq analyses indicate many signaling pathways in B progenitors are STAP-2 dependent. These findings suggest STAP-2 modulates formation of B lymphocytes in demand conditions. Further study of this adapter protein could suggest ways to speed recovery of humoral immunity following chemotherapy or transplantation. To determine the molecular basis for the inefficient B lymphopoiesis in STAP-2 Tg BM, transcriptome analyses were used to identify the pathways regulated by STAP-2 under hematological stress. We evaluated the global gene expression profile of pre-B cells derived from WT and Tg BM under steady-state as well as WT and KO BM 1 month after transplantation by RNA-seq experiments.