The E2A gene products belong to a class of helix-loop-helix (HLH) proteins, also named E-proteins. Members of the E-proteins include E12, E47, E2-2 and HEB. The DNA binding activities of the E- proteins are regulated by a distinct class of antagonistic HLH proteins, named Id gene products. Four Id genes are present in the mammalian genome, designated as Id1-4. E47 levels are high in T cell progenitors where they act to promote TCR2 gene rearrangement, induce the expression of genes involved in pre-TCR signaling and suppress proliferation. Once a pre-TCR has been generated, E47 levels decrease to permit developmental progression and cellular expansion. E47 expression also prevents the development of lymphoma in thymocyte progenitors. In this grant application we would examine how E- and Id protein activities are regulated to control developmental progression and suppress the development of lymphoma.
During previous studies we have demonstrated that a class of DNA binding proteins, named E- proteins are important for the development of white blood cells. We have also shown that the E- proteins make sure that white blood cells do not multiply inappropriately in healthy individuals. But mutations can make the E-proteins inactive. Such mutations can ultimately result in the development of lymphoid malignancies. The proposed studies would provide insight into how mutations in the genome of white blood cells lead to the development of lymphoma and should provide novel strategies for the treatment of human T cell leukemias.
|Miyazaki, Masaki; Miyazaki, Kazuko; Chen, Shuwen et al. (2015) The E-Id protein axis modulates the activities of the PI3K-AKT-mTORC1-Hif1a and c-myc/p19Arf pathways to suppress innate variant TFH cell development, thymocyte expansion, and lymphomagenesis. Genes Dev 29:409-25|
|Lucas, Joseph S; Bossen, Claudia; Murre, Cornelis (2011) Transcription and recombination factories: common features? Curr Opin Cell Biol 23:318-24|
|Miyazaki, Masaki; Rivera, Richard R; Miyazaki, Kazuko et al. (2011) The opposing roles of the transcription factor E2A and its antagonist Id3 that orchestrate and enforce the naive fate of T cells. Nat Immunol 12:992-1001|
|Mercer, Elinore M; Lin, Yin C; Benner, Christopher et al. (2011) Multilineage priming of enhancer repertoires precedes commitment to the B and myeloid cell lineages in hematopoietic progenitors. Immunity 35:413-25|
|Mercer, Elinore M; Lin, Yin C; Murre, Cornelis (2011) Factors and networks that underpin early hematopoiesis. Semin Immunol 23:317-25|
|Lin, Yin C; Jhunjhunwala, Suchit; Benner, Christopher et al. (2010) A global network of transcription factors, involving E2A, EBF1 and Foxo1, that orchestrates B cell fate. Nat Immunol 11:635-43|
|Heinz, Sven; Benner, Christopher; Spann, Nathanael et al. (2010) Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell 38:576-89|