Modeling of C/EBPalpha Mutant Acute Myeloid Leukemia Reveals a Common Expression Signature of Committed Myeloid Leukemia-Initiating Cells

Cancer Cell. 2008 Apr;13(4):299-310. doi: 10.1016/j.ccr.2008.02.008.

Abstract

Mutations in the CEBPA gene are present in 7%-10% of human patients with acute myeloid leukemia (AML). However, no genetic models exist that demonstrate their etiological relevance. To mimic the most common mutations affecting CEBPA-that is, those leading to loss of the 42 kDa C/EBPalpha isoform (p42) while retaining the 30kDa isoform (p30)-we modified the mouse Cebpa locus to express only p30. p30 supported the formation of granulocyte-macrophage progenitors. However, p42 was required for control of myeloid progenitor proliferation, and p42-deficient mice developed AML with complete penetrance. p42-deficient leukemia could be transferred by a Mac1+c-Kit+ population that gave rise only to myeloid cells in recipient mice. Expression profiling of this population against normal Mac1+c-Kit+ progenitors revealed a signature shared with MLL-AF9-transformed AML.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CCAAT-Enhancer-Binding Protein-alpha / deficiency
  • CCAAT-Enhancer-Binding Protein-alpha / genetics
  • CCAAT-Enhancer-Binding Protein-alpha / metabolism*
  • Cell Differentiation
  • Disease Progression
  • Gene Expression Profiling
  • Gene Expression Regulation, Leukemic*
  • Granulocytes / cytology
  • Leukemia, Myelomonocytic, Acute / genetics*
  • Leukemia, Myelomonocytic, Acute / pathology*
  • Macrophage-1 Antigen / metabolism
  • Mice
  • Mice, Knockout
  • Models, Biological*
  • Mutant Proteins / metabolism*
  • Myeloid Progenitor Cells / pathology
  • Neoplasm Transplantation
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology*
  • Phenotype
  • Protein Isoforms / metabolism
  • Proto-Oncogene Proteins c-kit / metabolism

Substances

  • CCAAT-Enhancer-Binding Protein-alpha
  • Macrophage-1 Antigen
  • Mutant Proteins
  • Protein Isoforms
  • Proto-Oncogene Proteins c-kit