Barbara L Kee

The development of mature hematopoietic cells requires the coordinated activity of many transcription factors that regulate differentiation, proliferation, and survival. My lab is interested in understanding how these processes are controlled during commitment of multipotent hematopoietic progenitor cells to the lymphoid lineages. We have focused on the basic helix-loop-helix transcription factors encoded by the E2A gene and their antagonists, the Id proteins. The E2A gene products are required for proper B and T lymphocyte development whereas Id2 is required for Natural Killer cell and Lymphoid Tissue initiating cell development. All of these lineages are thought to develop from a common lymphoid progenitor (CLP), suggesting that control of E2A activity may play a direct role in the lineage choice of CLPs. We have determined that E2A proteins are required for B-lymphocyte development, in part, because they induce the expression of EBF, another transcription factor that promotes B-lineage commitment. In addition to their role in the regulation of EBF, E2A proteins are required for optimal proliferation and expression of N-myc in response to cytokine stimulation. Therefore, E2A proteins link differentiation of multipotent cells into the B-lymphocyte lineage with the ability to proliferate in response to external factors.

E2A proteins are also required for proper T lympocyte lineage commitment and in their absence only a few T cells develop. Regardless, E2A-/- mice succumb to T cell lymphoma within the first 3-6 months of life. We have identified a number of E2A target genes that may function in T lymphocyte lineage commitment and/or the suppression of T cell lymphoma and we are currently characterizing the function of these proteins in lymphopoiesis.

The development of mature hematopoietic cells requires the coordinated activity of many transcription factors that regulate differentiation, proliferation, and survival. My lab is interested in understanding how these processes are controlled during commitment of multipotent hematopoietic progenitor cells to the lymphoid lineages. We have focused on the basic helix-loop-helix transcription factors encoded by the E2A gene and their antagonists, the Id proteins. The E2A gene products are required for proper B and T lymphocyte development whereas Id2 is required for Natural Killer cell and Lymphoid Tissue initiating cell development. All of these lineages are thought to develop from a common lymphoid progenitor (CLP), suggesting that control of E2A activity may play a direct role in the lineage choice of CLPs. We have determined that E2A proteins are required for B-lymphocyte development, in part, because they induce the expression of EBF, another transcription factor that promotes B-lineage commitment. In addition to their role in the regulation of EBF, E2A proteins are required for optimal proliferation and expression of N-myc in response to cytokine stimulation. Therefore, E2A proteins link differentiation of multipotent cells into the B-lymphocyte lineage with the ability to proliferate in response to external factors.

E2A...

Dias S, Xu W, McGregor S, Kee B. (2008) Transcriptional regulation of lymphocyte development. Curr Opin Genet Dev. in press. Epub. Sept. 5, 2008.  Link

Dias S, Mansson R, Gurbuxani S, Sigvardsson M, and BL Kee. (2008) E2A proteins promote development of lymphoid-primed multipotent progenitors. Immunity 29:217-227.  Link

Boos MD, Ramirez K, Kee BL. (2008) Extrinsic and intrinsic regulation of early natural killer cell development. Immunol Res. 40:193-207.  Link

Bhalla S, Spaulding C, Brumbaugh RL, Zagort DE, Massari ME, Murre C, Kee BL. (2008) Differential roles for the E2A activation domains in B lymphocytes and macrophages. J. Immunol. 180:1694-1703.   Link

Spaulding C, Reschly EJ, Zagort DE, Yashiro-Ohtani Y Beverly LJ, Capobianco AJ, Pear WS, Kee BL. (2007) Notch1 Co-opts Lymphoid Enhancer Factor 1 for Survival of T Cell Lymphomas. Blood 110(7):2650-2658.  Link

Nutt SL, Kee BL. (2007) The Transcriptional Regulation of B Cell Lineage Commitment. Immunity 26(6):715-725.  Link

Boos MD, Eberl G, Yokota Y, Kee BL. (2007) Mature Natural Killer Cell and Lymphoid Tissue Inducing Cell Development Requires Id2-Mediated Suppression of E Protein Activity. J. Exp. Med. 204(5):1119-1125.  Link

Xu W, Kee BL. (2007) Growth Factor Independence 1b(Gfi1b) is an E2A Target Gene that Modulates Gata3 in T Cell Lymphomas. Blood, 109(10):4406-4414.  Link

Reschly EJ, Spaulding C, Brumbaugh RL, Vilimas T, Aifantis I, Pear WS, Kee BL. (2006) Notch1 promotes survival of E2A-/- lymphomas through pre-T cell receptor-dependent and -independent mechanisms. Blood 107:4115-4121.  Link

Kee BL. (2005) Id3 Induces a Growth Arrest and Caspase-2-Dependent Apoptosis in B-Lymphocyte Progenitors. J. Immunol. 175(7):4518-4527  Link

Seet CS, Brumbaugh RL, Kee BL. (2004) Early B cell factor promotes B lymphopoiesis with reduced interleukin 7 responsiveness in the absence of E2A. J. Exp. Med. 199(12):1689-1700  Link

Kee BL, Bain G, Murre C. (2002) IL-7Ralpha and E47: independent pathways required for development of mulipotent lymphoid progenitors. EMBO J. 21:103-113  Link

Dias S, Xu W, McGregor S, Kee B. (2008) Transcriptional regulation of lymphocyte development. Curr Opin Genet Dev. in press. Epub. Sept. 5, 2008.  Link

Dias S, Mansson R, Gurbuxani S, Sigvardsson M, and BL Kee. (2008) E2A proteins promote development of lymphoid-primed multipotent progenitors. Immunity 29:217-227.  Link

Boos MD, Ramirez K, Kee BL. (2008) Extrinsic and intrinsic regulation of early natural killer cell development. Immunol Res. 40:193-207.  Link

Bhalla S, Spaulding C, Brumbaugh RL, Zagort DE, Massari ME, Murre C, Kee BL. (2008) Differential roles for the E2A activation domains in B lymphocytes and macrophages. J. Immunol. 180:1694-1703.   Link

Spaulding C, Reschly EJ, Zagort DE, Yashiro-Ohtani Y Beverly LJ, Capobianco AJ, Pear WS, Kee BL. (2007) Notch1 Co-opts Lymphoid Enhancer Factor 1 for Survival of T Cell Lymphomas. Blood 110(7):2650-2658.  Link