Two types of C/EBPα mutations play distinct but collaborative roles in leukemogenesis: lessons from clinical data and BMT models

Blood. 2011 Jan 6;117(1):221-33. doi: 10.1182/blood-2010-02-270181. Epub 2010 Sep 30.


Two types of mutations of a transcription factor CCAAT-enhancer binding protein α (C/EBPα) are found in leukemic cells of 5%-14% of acute myeloid leukemia (AML) patients: N-terminal mutations expressing dominant negative p30 and C-terminal mutations in the basic leucine zipper domain. Our results showed that a mutation of C/EBPα in one allele was observed in AML after myelodysplastic syndrome, while the 2 alleles are mutated in de novo AML. Unlike an N-terminal frame-shift mutant (C/EBPα-N(m))-transduced cells, a C-terminal mutant (C/EBPα-C(m))-transduced cells alone induced AML with leukopenia in mice 4-12 months after bone marrow transplantation. Coexpression of both mutants induced AML with marked leukocytosis with shorter latencies. Interestingly, C/EBPα-C(m) collaborated with an Flt3-activating mutant Flt3-ITD in inducing AML. Moreover, C/EBPα-C(m) strongly blocked myeloid differentiation of 32Dcl3 cells, suggesting its class II mutation-like role in leukemogenesis. Although C/EBPα-C(m) failed to inhibit transcriptional activity of wild-type C/EBPα, it suppressed the synergistic effect between C/EBPα and PU.1. On the other hand, C/EBPα-N(m) inhibited C/EBPα activation in the absence of PU.1, despite low expression levels of p30 protein generated by C/EBPα-N(m). Thus, 2 types of C/EBPα mutations are implicated in leukemo-genesis, involving different and cooperating molecular mechanisms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Apoptosis
  • Blotting, Western
  • Bone Marrow Transplantation
  • CCAAT-Enhancer-Binding Protein-alpha / genetics*
  • CCAAT-Enhancer-Binding Protein-alpha / metabolism
  • Cell Differentiation
  • Cell Proliferation
  • Disease Models, Animal*
  • Electrophoretic Mobility Shift Assay
  • Female
  • Flow Cytometry
  • Humans
  • Leukemia, Myeloid, Acute / etiology*
  • Leukemia, Myeloid, Acute / pathology*
  • Leukemia, Myeloid, Acute / therapy
  • Luciferases / metabolism
  • Male
  • Mice
  • Middle Aged
  • Mutation / genetics*
  • Myelodysplastic Syndromes / etiology*
  • Myelodysplastic Syndromes / pathology*
  • Myelodysplastic Syndromes / therapy
  • Polymerase Chain Reaction
  • Polymorphism, Single-Stranded Conformational
  • RNA, Messenger / genetics
  • Survival Rate
  • Transcriptional Activation


  • CCAAT-Enhancer-Binding Protein-alpha
  • RNA, Messenger
  • Luciferases