Transcriptional Repression of C/EBPα by Histone Deacetylases in Acute Myeloid Leukemia

  • B. Steffen
  • M. Ruthardt
  • K. Becker
  • S. Klümpen
  • M. Möller
  • W. E. Berdel
  • H. Serve
  • C. Müller-Tidow
Conference paper
Part of the Haematology and Blood Transfusion Hämatologie und Bluttransfusion book series (HAEMATOLOGY, volume 41)

Abstract

In acute myeloid leukemia (AML), fusion proteins such as AMLl-ETO recruit co-repressors and histone deacetylases (HDACs) to their target genes. We compared gene expression in fresh AML blasts with and without HDAC inhibition by Trichostatin A (TSA) to identify genes that are repressed by HDAC dependent mechanisms. After exposure to TSA, C/EBPa expression in leukemic blasts increased up to ten-fold in 31% (5/16) of the analyzed AML samples. For several other transcription factors (C/EBPε, Hox A10, AMLl, PBX1, MLL, HLX), no induction by TSA was found. We also analyzed whether C/EBPα expression was directly regulated by AML associated fusion proteins in inducibly transfected U937 cells. Expression of C/EBPa was significantly repressed by AMLl-ETO and PML-RARα. Interestingly, TSA led to C/EBPa induction in U937 cells expressing PML-RARa, but not in PLZF-RARa or AML1- ETO containing cells. Taken together, these findings provide further evidence for C/EBPα dysregulation in AML.

Keywords

DMSO Leukemia eDNA Sulindac SAHA 

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References

  1. 1.
    Tenen DG, Hromas R, Licht JD, Zhang DE, Transcription factors, normal myeloid development, and leukemia. Blood. 1997; 90:489–519PubMedGoogle Scholar
  2. 2.
    Müller C, Yang R., Park DJ, Serve H, Berdel WE, Koeffler HP. The aberrant fusion proteins PML-RARα and PLZF-RARα contribute to the overexpression of cyclin Al in acute promyelocytic leukemia. Blood. 2000; 96:3894–3899PubMedGoogle Scholar
  3. 3.
    Downing JR. The AMLl-ETO chimaeric transcription factor in acute myeloid leukaemia: biology and clinical significance. Br J Haematol. 1999; 106:296–308PubMedCrossRefGoogle Scholar
  4. 4.
    Melnick A, Licht JD. Deconstructing a Disease: RARα, its Fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood. 1999; 93:3167–3215PubMedGoogle Scholar
  5. 5.
    Ferrara FF, Fazi F, Bianchini A et al. Histone dea- cetylase-targeted treatment restores retinoic acid signaling and differentiation in acute myeloid leukemia. Cancer Res 2001; 61:2–7PubMedGoogle Scholar
  6. 6.
    Müller-Tidow C, Metzger R, Kiigler K et al. Cyclin E is the only cyclin-dependent kinase 2-associated cyclin that predicts metastasis and survival in early stage non-small cell lung cancer. Cancer Res. 2001 Jan 15; 61(2):647–53Google Scholar
  7. 7.
    Müller C, Readhead C, Diederichs S et al. Methyla- tion of the cyclin Al promoter correlates with gene silencing in somatic cell lines, while tissue- specific expression of cyclin Al is methylation independent. Mol Cell Biol. 2000; 20:3316–3329PubMedCrossRefGoogle Scholar
  8. 8.
    Bieche I, Laurendeau I, Tozlu S et al. Quantitation of MYC gene expression in sporadic breast tumors with a real-time reverse transcription-PCR assay. Cancer Res. 1999; 59:2759–65PubMedGoogle Scholar
  9. 9.
    Finnin MS, Donigian JR, Cohen A et al. Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature. 1999; 401:188–93PubMedCrossRefGoogle Scholar
  10. 10.
    Wang J, Saunthararajah Y, Redner RL, Liu JM. Inhibitors of histone deacetylase relieve ETO-media- ted repression and induce differentiation of AMLl-ETO leukemia cells. Cancer Res 1999; 59:2766–2769PubMedGoogle Scholar
  11. 11.
    Mariadason JM, Corner GA, Augenlicht LH. Genetic reprogramming in pathways of colonic cell maturation induced by short chain fatty acids: comparison with trichostatin A, sulindac, and cur- cumin and implications for chemoprevention of colon cancer. Cancer Res. 2000; 60:4561–4572PubMedGoogle Scholar
  12. 12.
    Radomska HS, Huettner CS, Zhang P, Cheng T, Scadden DT, Tenen DG. CCAAT/enhancer binding protein alpha is a regulatory switch sufficient for induction of granulocytic development from bipotential myeloid progenitors. Mol Cell Biol. 1998; 18:4301–14PubMedGoogle Scholar
  13. 13.
    Pabst T, Mueller BU, Zhang P et al. Dominant-negative mutations of CEBPA encoding CCAAT/ enhancer binding protein-a (C/EBPa), in acute myeloid leukemia. Nat Genet 2001; 27:263–270PubMedCrossRefGoogle Scholar
  14. 14.
    Westendorf J J, Yamamoto CM, Lenny N, Downing JR, Selsted ME, Hiebert SW. The t(8;21) fusion product, AML-1-ETO, associates with C/EBP-alpha, inhibits C/EBP-alpha-dependent transcription, and blocks granulocytic differentiation. Mol Cell Biol. 1998; 18:322–33PubMedGoogle Scholar
  15. 15.
    Pabst T, Mueller BU, Harakawa N et al. AML1-ETO downregulates the granulocytic diffentiation factor C/EBPα in t(8;21) myeloid leukemia. Nat Med. 2001; 7:444–51PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2003

Authors and Affiliations

  • B. Steffen
    • 1
    • 2
  • M. Ruthardt
    • 1
    • 2
  • K. Becker
    • 1
    • 2
  • S. Klümpen
    • 1
    • 2
  • M. Möller
    • 1
    • 2
  • W. E. Berdel
    • 1
    • 2
  • H. Serve
    • 1
    • 2
  • C. Müller-Tidow
    • 1
    • 2
  1. 1.Department of Internal Medicine, Hematology/OncologyUniversity of MünsterGermany
  2. 2.Department of Medicine IIIUniversity of FrankfurtFrankfurt am MainGermany

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