This revised Program Project is directed at the mechanisms which control lymphocyte proliferation and differentiation. The four interactive projects (headed by five independent project leaders) and the SCID mouse core which comprise the scientific components of this Program Project study molecular and cellular processes in normal lymphocyte maturation and the disregulation of these processes in human immune deficiency and malignancy. Dr. Randolph Wall (Project #1. B Cell Genes: Expression, Regulation and Function) continues the cloning of B cell specific genes and the characterization of their function in the B cell growth and development. The new project headed by Dr. Owen Witte and Dr. Chris Denny (Project #2. Analysis of Lymphoid Malignancy Translocation Oncogenes Activated by Large DNA Transfer) is developing approaches for introducing large DNA segments into cells to study the molecular mechanisms in the translocations of the c-MYC proto-oncogene in Burkitt lymphoma and the ABL proto-oncogene in chronic myelogenous leukemia. Dr. Jon Braun's project (Project #3. lg Variable Region Hypermutation in Human B Lymphocytes) continues to study the processes in antibody diversification by variable region hypermutation and the maturation of human memory B cells. Dr. Saxton's ongoing project (Project #4. B Cell Responses in Common Variable Immunodeficiency) is studying the defects which block B cell maturation to immunoglobulin secretion in common variable immunodeficiency (CVI). All these projects utilize a newly established SCID mouse facility (Project #6. SCID and SCID- Human mouse Core), headed by Drs. Saxon and Witte, for analyzing the reconstitution of immune responses by lymphoid tissues or cells and for characterizing transformed or malignant cells. The molecular, cellular and SCID mouse in vivo reconstitution approaches in this Program Project constitute a powerful combination for defining the processes which regulate the growth, development and oncogenic transformation of lymphoid cells. Understanding these regulatory mechanisms will ultimately allow manipulation of immune responses to control disease and cancer.