B cell development starts in bone marrow with the commitment of hematopoietic progenitors to the B cell lineage. In murine models, the IL-7 and preBCR receptors, and the signaling pathways and transcription factors that they regulate, control commitment and maintenance along the B cell pathway. E2A, EBF1, PAX5, and Ikaros are among the most important transcription factors controlling early development and thereby conditioning mice homeostatic B cell lymphopoiesis. Importantly, their gain or loss of function often results in malignant development in humans, supporting conserved roles for these transcription factors. B cell acute lymphoblastic leukemia is the most common cause of pediatric cancer, and it is characterized by unpaired early B cell development resulting from genetic lesions in these critical signaling pathways and transcription factors. Fine mapping of these genetic abnormalities is allowing more specific treatments, more accurately predicting risk profiles for this disease, and improving survival rates. 1. Introduction The main function of mature immunocompetent B cells is to make antibodies; therefore, they are responsible for the adaptive humoral immune response. Formation of these mature B cells is a highly ordered multistep process that in adult mammals starts in bone marrow with the commitment of hematopoietic stem cells to the B cell lineage and ends with formation of mature B cells in secondary lymphoid organs. This developmental process was once thought to be inflexible, unidirectional, and irreversible, but recent lines of evidence support a higher level of plasticity to the differentiating cell. Several transcription factors (TFs) play critical roles in commitment and maintenance along the B cell pathway, and their gain or loss affects homeostatic B cell lymphopoiesis and often results in malignant transformation. 2. The Early Stages of B Cell Development B cells express receptors (BCRs) to various antigens; each BCR is uniquely specialized to recognize and counteract a particular new or recurrent pathogen. The main goal of B cell development is to generate B cells expressing a diverse repertoire of BCRs. This receptor is a membrane-bound immunoglobulin (Ig) consisting of a heterodimer of identical pairs of the Ig heavy and light chains, which are responsible for the clonal diversity of the B cell repertoire. The Ig heavy and light chain heterodimer is, however, unable to generate signals to trigger biological responses after antigen binding; this function is mediated by the disulfide-coupled heterodimer of Igα (CD79a) and Igβ
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