Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The emergence of a C/EBPα mutation in the clonal evolution of MDS towards secondary AML

Abstract

Recently, mutations in the transcription factor CCAAT/ enhancer binding protein alpha (C/EBPα) have been described in acute myeloid leukemia (AML). We performed a mutational analysis of the C/EBPα gene in the myelodysplastic syndromes and AML with antecedent MDS. No mutations were found in patients with refractory anemia (0/27), refractory anemia with ringed sideroblasts (0/7), refractory anemia with excess of blasts (RAEB 0/16) or chronic myelomonocytic leukemia (CMML 0/5). One out of 13 patients with RAEB-T/AML secondary to MDS showed a mutation in the C/EBPα gene. In this patient a 4 bp insertion disrupted codon 69 in one allele. This novel +1 frame shift is predicted to result in a truncated protein of 107 amino acids. However, the dominant protein translated was the C/EBPα isoform p30, which was previously shown to inhibit the DNA-binding and transactivation properties of C/EBPα p42. Interestingly this mutation could not be detected at diagnosis in the initial RAEB and RAEB-T stage. The mutation appeared at relapse after chemotherapy for RAEB-T. We conclude that the C/EBPα mutation was not essential for the initial blast accumulation. The emergence of a bast clone carrying a C/EBPα mutation at relapse indicates that this mutation may confer a growth advantage in a myeloid cell with an established differentiation block.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

References

  1. Zhang DE, Zhang P, Wang ND, Hetherington CJ, Darlington, GJ & Tenen DG . Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein α-deficient mice. Proc Natl Acad Sci USA, 1997; 94: 569–574.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. 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: 4301–4314.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Smith LT, Hohaus S, Gonzalez DAA, Dziennis SE & Tenen DG . PU.1 (Spi-1) and C/EBP alpha regulate the granulocyte colony-stimulating factor receptor promoter in myeloid cells. Blood 1996; 88: 1234–1247.

    CAS  PubMed  Google Scholar 

  4. Oelgeschlager M, Nuchprayoon I, Luscher B & Friedman AD . C/EBP, c-myb and PU.1 cooperate to regulate the neutrophil elastase promoter. Mol Cell Biol 1996; 16: 4717–4725.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Pabst T, Mueller BU, Zhang P, Radomska HS, Narravula S, Schnittger S, Behre G, Hiddemann W & Tenen DG . Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-α, in acute myeloid leukemia. Nat Genet 2001; 27: 263–270.

    Article  CAS  PubMed  Google Scholar 

  6. Gombart AF, Hofmann W-K, Kawano S, Takeuchi S, Krug U, Kwok SH, Larsen RJ, Asou H, Miller CW, Hoelzer D & Koeffler HP . Mutations in the gene encoding the transcription factor CCAAT/enhancer binding protein alpha in myelodysplastic syndromes and acute myeloid leukemia. Blood 2002; 99: 1332–1340.

    Article  CAS  PubMed  Google Scholar 

  7. Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, Lister TA & Bloomfield CD . World Health Organisation classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Commitee meeting-Arlie House, Virginia, November 1997. J Clin Oncol 1999; 17: 3835–3849.

    Article  CAS  PubMed  Google Scholar 

  8. Orita M, Iwahhana H, Kanazawa H, Hayashi K & Sekiya T. Detection of polymorphisms of human DNA by gel electrophoresis as single strand conformation polymorphisms. Proc Natl Acad Sci USA 1996; 86: 2766–2770.

    Article  Google Scholar 

  9. Verbeek W, Spirin K, Hatta Y, Miller C, Kawamata N, Takeuchi S, Koike M, Asou H, Simpson JF & Koeffler HP. DPC4/SMAD 4 in non-pancreatic tumors with frequent LOH 18q21 and in hematological malignancies. Int J Oncol 1997; 10: 257–260.

    CAS  PubMed  Google Scholar 

  10. Verbeek W, Lekstrom-Himes J, Park DJ, Dang PM-C, Vuong P, Kawano S, Babior BM, Xanthopoulos K & Koeffler HP. Myeloid transcription factor C/EBPε is involved in the positive regulation of lactoferrin gene expression in neutrophils. Blood 1999; 94: 3141–3150.

    CAS  PubMed  Google Scholar 

  11. Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DA, Gralnick HR & Sultan C . Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 1982; 51: 189–199.

    Article  CAS  PubMed  Google Scholar 

  12. Friedman AD & McKnight SL . Identification of two polypeptide segments of CCAAT enhancer binding protein required for transcriptional activation of the serum albumin gene. Genes Dev 1990; 4: 1416–1426.

    Article  CAS  PubMed  Google Scholar 

  13. Nerlov C & Ziff EB . Three levels of functional interaction determine the activity of CCAAT enhancer binding protein alpha on the serum albumin promoter. Genes Dev 1994; 8: 350–362.

    Article  CAS  PubMed  Google Scholar 

  14. Hendricks-Taylor LR & Darlington GJ . The CCAAT/enhancer-binding protein (C/EBPα) gene (CEBPA) maps to human chromosome 19q13.1 and the related nuclear factor NF IL-6 (C/EBPβ) gene (CEBPB) maps to human chromosome20q13.1. Genomics 1992; 4: 12–17.

    Article  Google Scholar 

  15. Strout MP, Marcucci G, Bloomfield CD & Caligiuri MA . The partial tandem duplication of ALL1 (MLL) is consistently generated by Alu-mediated homologous recombination in acute myeloid leukemia. Proc Natl Acad Sci USA 1998; 95: 2390–2395.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Osato M, Asou N, Abdalla E, Hoshini K, Yamasaki H, Okubo T, Suzushima H, Takatsuki K, Kanno T, Shigesada K & Ito Y . Biallelic and heterozygous point mutations in the runt domain of the AML1/PEBP2αB gene associated with myeloblastic leukemias. Blood 1999; 93: 1817–1824.

    CAS  PubMed  Google Scholar 

  17. Imai Y, Kurokawa M, Izutsu K, Hangaishi A, Takeuchi K, Maki K, Ogawa S, Chiba S, Mitani K & Hirai H . Mutations of the AML1 gene in myelodysplastic syndrome and their functional implications in leukemogenesis. Blood 2000; 96: 3154–3160.

    CAS  PubMed  Google Scholar 

  18. Lin FT, MacDougald OA, Diehl AM & Lane MD . A 30 kD alternative translation product of the CCAAT/enhancer binding protein alpha message: transcriptional activator lacking antimitotic activity. Proc Natl Acad Sci USA 1993; 90: 9606–9610.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Cao Z, Umek RM & McKnight . SL Regulated expression of three C/EBP isoforms during adipose conversion of 3T3-L1 cells. Genes Dev 1991; 5: 1538–1552.

    Article  CAS  PubMed  Google Scholar 

  20. Timchenko NA, Wilde M, Nakanishi M, Smith JR & Darlington GJ . CCAAT/enhancer binding protein alpha (C/EBPα) inhibits cell proliferation through the p21 (WAF/CIP-1/SDI-1) protein. Genes Dev 1996; 10: 804–815.

    Article  CAS  PubMed  Google Scholar 

  21. Slomiany BA, D’Arigo KL, Kelly MM & Kurtz DT . C/EBPα inhibits cell growth via direct repression of E2F-DP-mediated transcription. Mol Cell Biol 2000; 20: 5986–5997.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Johansen LM, Iwama A, Lodie TA, Sasaki K, Felsher DW, Golub TR & Tenen DG . c-myc is a critical target of C/EBPα in granulopoiesis. Mol Cell Biol 2001; 21: 3789–3806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Diaz MO, Le Beau MM, Harden A & Rowley JD . Trisomy 8 in human hematologic neoplasia and the c-myc and c-mos oncogenes. Leuk Res 1995; 9: 1437–1442.

    Article  Google Scholar 

Download references

Acknowledgements

This work was in part supported by the Kompetenznetzwerk Acute and Chronic Leukemias, Germany and the Dieter-Schlag-Stiftung for Leukemia Research.

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kaeferstein, A., Krug, U., Tiesmeier, J. et al. The emergence of a C/EBPα mutation in the clonal evolution of MDS towards secondary AML. Leukemia 17, 343–349 (2003). https://doi.org/10.1038/sj.leu.2402805

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2402805

Keywords

Search

Quick links