The E2A gene encodes two E protein/class I basic helix-loop-helix transcription factors, E12 and E47, that are essential for B lymphopoiesis. In addition to the DNA-binding and protein dimerization domain, the E proteins share two highly conserved transcription activation domains. In this study, we show that both activation domains are required for optimal E2A-dependent transcription. Surprisingly, however, neither activation domain is required for E2A to rescue B lymphopoiesis from E2A−/− hemopoietic progenitors, although the N terminus of E2A, which harbors some transcription capacity, is required. Therefore, the E protein activation domains function redundantly in promoting B cell development. In contrast, the N-terminal activation domain, AD1, is required for a newly described ability of E2A to suppress macrophage development in vitro. Our findings demonstrate distinct functionalities for the E protein activation domains in B lymphocytes and macrophages.

The E2A gene encodes two E protein/class I basic helix-loop-helix transcription factors, E12 and E47, that are essential for B lymphopoiesis. In addition to the DNA-binding and protein dimerization domain, the E proteins share two highly conserved transcription activation domains. In this study, we show that both activation domains are required for optimal E2A-dependent transcription. Surprisingly, however, neither activation domain is required for E2A to rescue B lymphopoiesis from E2A(-/-) hemopoietic progenitors, although the N terminus of E2A, which harbors some transcription capacity, is required. Therefore, the E protein activation domains function redundantly in promoting B cell development. In contrast, the N-terminal activation domain, AD1, is required for a newly described ability of E2A to suppress macrophage development in vitro. Our findings demonstrate distinct functionalities for the E protein activation domains in B lymphocytes and macrophages.

Oncogenic Notch1 mutations are found in most T-lineage acute lymphoblastic leukemias in humans and T-cell lymphomas in mice. However, the mechanism by which Notch1 promotes transformation or maintains malignant cell survival has not been determined fully. Here, we report that expression of the transcription factor lymphoid enhancer factor 1 (Lef1) is Notch dependent in murine T-cell lymphomas in vitro and in vivo, and that the intracellular domain of Notch1 (ICN1) is present at the Lef1 promoter. Lef1 expression is not Notch dependent in primary T-cell progenitors, but Lef1 mRNA is increased by ectopic expression of ICN1 in these cells. We show that Lef1 is required for survival of T-cell lymphoma lines, and that ectopic expression of Lef1 delays lymphoma cell death in the absence of Notch signaling, indicating that Lef1 is an important Notch target in these cells. Therefore, Notch1 co-opts Lef1 during the process of transformation to maintain survival of T-cell lymphomas.