Deletion of an AML1-ETO C-terminal NcoR/SMRT-interacting region strongly induces leukemia development

Proc Natl Acad Sci U S A. 2004 Dec 7;101(49):17186-91. doi: 10.1073/pnas.0406702101. Epub 2004 Nov 29.

Abstract

Normal blood-cell differentiation is controlled by regulated gene expression and signal transduction. Transcription deregulation due to chromosomal translocation is a common theme in hematopoietic neoplasms. AML1-ETO, which is a fusion protein generated by the 8;21 translocation that is commonly associated with the development of acute myeloid leukemia, fuses the AML1 runx family DNA-binding transcription factor to the ETO corepressor that associates with histone deacetylase complexes. Analyses have demonstrated that AML1-ETO blocks AML1 function and requires additional mutagenic events to promote leukemia. Here, we report that the loss of the molecular events of AML1-ETO C-terminal NCoR/SMRT-interacting domain transforms AML1-ETO into a potent leukemogenic protein. Contrary to full-length AML1-ETO, the truncated form promotes in vitro growth and does not obstruct the cell-cycle machinery. These observations suggest a previously uncharacterized mechanism of tumorigenesis, in which secondary mutation(s) in molecular events disrupting the function of a domain of the oncogene promote the development of malignancy.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Bone Marrow Cells / metabolism
  • Bone Marrow Transplantation
  • Cell Cycle
  • Cell Differentiation
  • Cell Proliferation
  • Cell Transformation, Neoplastic / genetics*
  • Core Binding Factor Alpha 2 Subunit
  • DNA-Binding Proteins / metabolism*
  • Leukemia, Myeloid / etiology
  • Leukemia, Myeloid / genetics*
  • Leukemia, Myeloid / pathology
  • Mice
  • Mice, Inbred Strains
  • Myeloid Cells / cytology
  • Nuclear Receptor Co-Repressor 2
  • Oncogene Proteins, Fusion / chemistry
  • Oncogene Proteins, Fusion / genetics*
  • Oncogene Proteins, Fusion / physiology
  • Protein Binding
  • RUNX1 Translocation Partner 1 Protein
  • Repressor Proteins / metabolism*
  • Sequence Deletion*
  • Transcription Factors / chemistry
  • Transcription Factors / genetics*
  • Transcription Factors / physiology
  • Transduction, Genetic

Substances

  • AML1-ETO fusion protein, human
  • Core Binding Factor Alpha 2 Subunit
  • DNA-Binding Proteins
  • NCOR2 protein, human
  • Ncor2 protein, mouse
  • Nuclear Receptor Co-Repressor 2
  • Oncogene Proteins, Fusion
  • RUNX1 Translocation Partner 1 Protein
  • Repressor Proteins
  • Transcription Factors