Initiation of MLL-rearranged AML is dependent on C/EBPα

J Exp Med. 2014 Jan 13;211(1):5-13. doi: 10.1084/jem.20130932. Epub 2013 Dec 23.

Abstract

MLL-fusion proteins are potent inducers of oncogenic transformation, and their expression is considered to be the main oncogenic driving force in ∼10% of human acute myeloid leukemia (AML) patients. These oncogenic fusion proteins are responsible for the initiation of a downstream transcriptional program leading to the expression of factors such as MEIS1 and HOXA9, which in turn can replace MLL-fusion proteins in overexpression experiments. To what extent MLL fusion proteins act on their own during tumor initiation, or if they collaborate with other transcriptional regulators, is unclear. Here, we have compared gene expression profiles from human MLL-rearranged AML to normal progenitors and identified the myeloid tumor suppressor C/EBPα as a putative collaborator in MLL-rearranged AML. Interestingly, we find that deletion of Cebpa rendered murine hematopoietic progenitors completely resistant to MLL-ENL-induced leukemic transformation, whereas C/EBPα was dispensable in already established AMLs. Furthermore, we show that Cebpa-deficient granulocytic-monocytic progenitors were equally resistant to transformation and that C/EBPα collaborates with MLL-ENL in the induction of a transcriptional program, which is also apparent in human AML. Thus, our studies demonstrate a key role of C/EBPα in MLL fusion-driven transformation and find that it sharply demarcates tumor initiation and maintenance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CCAAT-Enhancer-Binding Protein-alpha / genetics
  • CCAAT-Enhancer-Binding Protein-alpha / metabolism*
  • Cell Transformation, Neoplastic / metabolism*
  • Computational Biology
  • DNA Primers / genetics
  • Flow Cytometry
  • Gene Deletion
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / physiology*
  • Histone-Lysine N-Methyltransferase
  • Homeodomain Proteins / metabolism
  • Humans
  • Leukemia, Myeloid, Acute / metabolism*
  • Mice
  • Myeloid Ecotropic Viral Integration Site 1 Protein
  • Myeloid-Lymphoid Leukemia Protein / metabolism*
  • Neoplasm Proteins / metabolism
  • Oncogene Proteins, Fusion / metabolism*
  • Polymerase Chain Reaction

Substances

  • CCAAT-Enhancer-Binding Protein-alpha
  • DNA Primers
  • Homeodomain Proteins
  • KMT2A protein, human
  • MEIS1 protein, human
  • Meis1 protein, mouse
  • Myeloid Ecotropic Viral Integration Site 1 Protein
  • Neoplasm Proteins
  • Oncogene Proteins, Fusion
  • homeobox protein HOXA9
  • Myeloid-Lymphoid Leukemia Protein
  • Histone-Lysine N-Methyltransferase