Sox4 is a key oncogenic target in C/EBPα mutant acute myeloid leukemia

Cancer Cell. 2013 Nov 11;24(5):575-88. doi: 10.1016/j.ccr.2013.09.018. Epub 2013 Oct 31.

Abstract

Mutation or epigenetic silencing of the transcription factor C/EBPα is observed in ∼10% of patients with acute myeloid leukemia (AML). In both cases, a common global gene expression profile is observed, but downstream targets relevant for leukemogenesis are not known. Here, we identify Sox4 as a direct target of C/EBPα whereby its expression is inversely correlated with C/EBPα activity. Downregulation of Sox4 abrogated increased self-renewal of leukemic cells and restored their differentiation. Gene expression profiles of leukemia-initiating cells (LICs) from both Sox4 overexpression and murine C/EBPα mutant AML models clustered together but differed from other types of AML. Our data demonstrate that Sox4 overexpression resulting from C/EBPα inactivation contributes to the development of leukemia with a distinct LIC phenotype.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CCAAT-Enhancer-Binding Proteins / genetics*
  • CCAAT-Enhancer-Binding Proteins / metabolism
  • Cell Differentiation
  • Cell Proliferation
  • Cells, Cultured
  • Gene Expression Regulation, Leukemic*
  • Gene Knockdown Techniques
  • Hematopoietic Stem Cells / physiology
  • Humans
  • Leukemia, Myeloid, Acute / genetics*
  • Leukemia, Myeloid, Acute / pathology
  • Mice
  • Mice, Knockout
  • Mutation
  • Myeloid Cells / metabolism
  • Neoplasm Transplantation
  • Neoplastic Stem Cells / metabolism
  • Oncogenes
  • SOXC Transcription Factors / genetics*
  • SOXC Transcription Factors / metabolism
  • Transcriptome

Substances

  • CCAAT-Enhancer-Binding Proteins
  • CEBPA protein, human
  • SOX4 protein, human
  • SOXC Transcription Factors