Growth Factor Independence 1b (Gfi1b) is an E2A Target Gene that Modulates Gata3 in T Cell Lymphomas. (82.3)

Abstract

Abstract T cell development depends on the activity of multiple transcription factors, including E2A and Gata3. E2A proteins are required for normal T lymphopoiesis and to prevent T lymphocyte progenitor transformation. Ectopic expression of E2A proteins in E2A-deficient lymphomas results in growth arrest and apoptosis indicating that these cells remain responsive to the targets of E2A. We identify the transcriptional repressor Growth factor independence 1b (Gfi1b) as a target of E2A that promotes growth arrest and apoptosis in lymphomas. Gfi1b expression in primary T lymphocyte progenitors is dependent on E2A and excess Gfi1b prevents the outgrowth of T lymphocyte progenitors in vitro. We also find that Gfi1b represses expression of Gata3, a transcription factor whose appropriate regulation is required for survival of lymphomas and T lymphocyte progenitors. Ectopic expression of Gata3 in lymphomas promotes expression of Gfi1b indicating that these proteins may function in an auto-regulatory loop that maintains appropriate levels of Gata3. Therefore, we propose that E2A proteins prevent lymphoma cell expansion, at least in part, through regulation of Gfi1b and modulation of Gata3 expression.