C/EBPα and C/EBPε induce the monocytic differentiation of myelomonocytic cells with the MLL-chimeric fusion gene

H. Matsushita, H. Nakajima, Y. Nakamura, H. Tsukamoto, Y. Tanaka, G. Jin, M. Yabe, S. Asai, R. Ono, T. Nosaka, K. Sugita, A. Morimoto, Y. Hayashi, T. Hotta, K. Ando, H. Miyachi

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16 Citations (Scopus)

Abstract

CCAAT/enhancer binding proteins (C/EBPs) have an important function in granulocytic differentiation, and are also involved in the leukemogenesis of acute myeloid leukemia (AML). Their involvement in myelomonocytic leukemia, however, is still unclear. Therefore, the expression and function of C/EBPs in myelomonocytic cells with MLL-fusion genes were investigated. Retinoic acid (RA) induced monocytic differentiation in the myelomonocytic cell lines with MLL-fusion genes, THP-1, MOLM-14 and HF-6 cells, accompanied by monocytic differentiation with the upregulation of C/EBPα and C/EBPε. Monocytic differentiation by RA treatment was confirmed in primary AML cells using a clonogenic assay. When the activity of C/EBPα or C/EBPε was introduced into HF-6 cells, their cellular growth was arrested through differentiation into monocytes with the concomitant marked downregulation of Myc. Cebpe mRNA was upregulated by the induction of C/EBPα-ER, but not vice versa, thus suggesting that C/EBPε may have an important function in the differentiation process. Introduction of Myc isoforms into HF-6 cells partially antagonized the C/EBPs effects. These findings suggest that the ectopic expression of C/EBPε, as well as C/EBPα, can induce the monocytic differentiation of myelomonocytic leukemic cells with MLL-fusion gene through the downregulation of Myc, thus providing insight into the development of novel therapeutic approaches.

Original languageEnglish
Pages (from-to)6749-6760
Number of pages12
JournalOncogene
Volume27
Issue number53
DOIs
Publication statusPublished - 2008 Nov 13

Keywords

  • Acute myeloid leukemia
  • CCAAT/enhancer binding protein-α
  • CCAAT/enhancer binding protein-ε
  • Mixed lineage leukemia gene
  • Monocytic differentiation

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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  • Cite this

    Matsushita, H., Nakajima, H., Nakamura, Y., Tsukamoto, H., Tanaka, Y., Jin, G., Yabe, M., Asai, S., Ono, R., Nosaka, T., Sugita, K., Morimoto, A., Hayashi, Y., Hotta, T., Ando, K., & Miyachi, H. (2008). C/EBPα and C/EBPε induce the monocytic differentiation of myelomonocytic cells with the MLL-chimeric fusion gene. Oncogene, 27(53), 6749-6760. https://doi.org/10.1038/onc.2008.285