Attenuation of AML1-ETO cellular dysregulation correlates with increased leukemogenic potential.

Academic Article

Abstract

  • AML1-ETO (RUNX1-ETO) fusion proteins are generated by the 8;21 translocation, commonly found in acute myeloid leukemia, which fuses the AML1 (RUNX1) and ETO (MTG8, RUNX1T1) genes. Previous studies have shown that AML1-ETO interferes with AML1 function but requires additional cooperating mutations to induce leukemia development. In mouse models, AML1-ETO forms lacking the C-terminus have been shown to have greatly enhanced leukemogenic potential. Here, we investigate the role of 2 AML1-ETO C-terminal-interacting proteins, N-CoR, a transcriptional corepressor, and SON, a splicing/transcription factor required for cell cycle progression, in AML1-ETO-induced leukemia development. AML1-ETO-W692A loses N-CoR binding at NHR4, displays attenuated transcriptional repression ability and decreased cellular dysregulation, and promotes leukemia in vivo. These results support the importance of the degree of dysregulation by AML1-ETO in cellular transformation and demonstrate that AML1-ETO-W692A can be used as an effective experimental model for determining which factors compromise the leukemogenic potential of AML1-ETO.
  • Published In

  • Blood  Journal
  • Keywords

  • Animals, Cell Transformation, Neoplastic, Cells, Cultured, Core Binding Factor Alpha 2 Subunit, Down-Regulation, Gene Expression Regulation, Leukemic, HEK293 Cells, Humans, K562 Cells, Leukemia, Mice, Mice, Inbred C57BL, Nuclear Receptor Co-Repressor 1, Oncogene Proteins, Fusion, Protein Binding, RUNX1 Translocation Partner 1 Protein
  • Digital Object Identifier (doi)

    Author List

  • DeKelver RC; Yan M; Ahn E-Y; Shia W-J; Speck NA; Zhang D-E
  • Start Page

  • 3714
  • End Page

  • 3717
  • Volume

  • 121
  • Issue

  • 18