The importance of E2A transcription factors in T cell development has been demonstrated in studies of E2A-deficient mice, which display abnormal T cell development and a high frequency of T cell lymphomas. Because E2A expression is not restricted to the T cell lineage, the primary cause of the T cell phenotype in E2A-deficient mice was not fully determined. To further investigate the role of E2A in T cell lineage, we generated mice with the E2A gene disrupted exclusively during thymocyte development using the Cre-lox system. We show that this system allows E2A gene disruption to occur throughout the double-negative stage of thymocyte development. E2A deletion appears to be completed before development reaches the double-positive stage. Consistent with the gene disruption, these mice reveal a T cell intrinsic role for E2A during the transition from the double-negative stage to the double-positive stage of thymocyte development. In contrast to germline E2A knockout mice, conditional E2A knockout mice do not develop T cell lymphoma. This work establishes a new model for further investigating E2A function in T cell development and leukemiogenesis.

Lymphocytes are derived from hematopoietic stem cells (HSC) following a series of regulated differentiation events. Multipotent HSCs become committed to the B cell lineage in bone marrow and the T cell lineage in the thymus after receiving appropriate signals from the corresponding microenvironment. These committed lymphoid cells must then undergo V(D)J recombination at the immunoglobulin gene or T cell receptor gene locus resulting in clonal production of functional B or T lymphocytes, respectively. Lymphocyte commitment and differentiation are accompanied by programmed gene expression or repression events which are driven by lineage and stage specific transcription factors. The basic-helix-loop-helix (bHLH) transcription factors encoded by the E2A gene are involved in several differentiation events during B and T cell development, including lineage commitment, initiation of V(D)J recombination, and antigen receptor mediated proliferation and differentiation. Several recent reviews have provided a comprehensive discussion of biochemical, cellular, and genetic research on E2A function in lymphocyte development (1,2). Here, we only discuss some of the genetic approaches our laboratory (except where it is noted) has undertaken to investigate the molecular pathways mediated by E2A transcription factors in lymphocyte development.