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CEBPA methylation and mutation in myelodysplastic syndrome

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Abstract

Aberrant methylation of CCAAT/enhancer-binding protein alpha (CEBPA) promoter has been observed in acute myeloid leukemia. However, little is known about CEBPA promoter in myelodysplastic syndrome (MDS). The purpose of this study was to investigate the alteration of CEBPA promoter in MDS patients and further determine the association with CEBPA expression and mutation. CEBPA promoter was significantly methylated in 105 MDS patients compared to 22 controls (median 0.016 vs. 0.000) (P < 0.0001). Receiver operating characteristic curve analysis discriminated all patients or cytogenetically normal patients from normal controls. Three cases (3 %) were identified with single-mutated CEBPA and one (1 %) with double-mutated CEBPA. CEBPA methylation and mutation occurred mutually exclusive. No significant correlation was found between CEBPA expression and methylation (P = 0.586). Our findings indicate that CEBPA methylation is a common event in MDS, but could not act as a prognostic biomarker for MDS patients.

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References

  1. Koschmieder S, Halmos B, Levantini E, Tenen DG. Dysregulation of the C/EBPalpha differentiation pathway in human cancer. J Clin Oncol. 2009;27:619–28.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Ossipow V, Descombes P, Schibler U. CCAAT/enhancer-binding protein mRNA is translated into multiple proteins with different transcription activation potentials. Proc Natl Acad Sci USA. 1993;90:8219–23.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Calkhoven CF, Bouwman PR, Snippe L, Ab G. Translation start site multiplicity of the CCAAT/enhancer binding protein alpha mRNA is dictated by a small 5′ open reading frame. Nucl Acids Res. 1994;22:5540–7.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Cammenga J, Mulloy JC, Berguido FJ, MacGrogan D, Viale A, Nimer SD. Induction of C/EBPalpha activity alters gene expression and differentiation of human CD34+ cells. Blood. 2003;101:2206–14.

    Article  CAS  PubMed  Google Scholar 

  5. Keeshan K, Santilli G, Corradini F, Perrotti D, Calabretta B. Transcription activation function of C/EBPalpha is required for induction of granulocytic differentiation. Blood. 2003;102:1267–75.

    Article  CAS  PubMed  Google Scholar 

  6. Zhang P, Iwasaki-Arai J, Iwasaki H, Fenyus ML, Dayaram T, Owens BM, Shigematsu H, Levantini E, Huettner CS, Lekstrom-Himes JA, Akashi K, Tenen DG. Enhancement of hematopoietic stem cell repopulating capacity and self-renewal in the absence of the transcription factor C/EBP alpha. Immunity. 2004;21:853–63.

    Article  CAS  PubMed  Google Scholar 

  7. Zhang DE, Hetherington CJ, Meyers S, Rhoades KL, Larson CJ, Chen HM, Hiebert SW, Tenen DG. CCAAT enhancer-binding protein (C/EBP) and AML1 (CBF alpha2) synergistically activate the macrophage colony-stimulating factor receptor promoter. Mol Cell Biol. 1996;16:1231–40.

    CAS  PubMed Central  PubMed  Google Scholar 

  8. Heath V, Suh HC, Holman M, Renn K, Gooya JM, Parkin S, Klarmann KD, Ortiz M, Johnson P, Keller J. C/EBPalpha deficiency results in hyperproliferation of hematopoietic progenitor cells and disrupts macrophage development in vitro and in vivo. Blood. 2004;104:1639–47.

    Article  CAS  PubMed  Google Scholar 

  9. Schepers H, Wierenga AT, van Gosliga D, Eggen BJ, Vellenga E, Schuringa JJ. Reintroduction of C/EBPalpha in leukemic CD34+ stem/progenitor cells impairs self-renewal and partially restores myelopoiesis. Blood. 2007;110:1317–25.

    Article  CAS  PubMed  Google Scholar 

  10. 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-alpha (C/EBPalpha), in acute myeloid leukemia. Nat Genet. 2001;27:263–70.

    Article  CAS  PubMed  Google Scholar 

  11. Kirstetter P, Schuster MB, Bereshchenko O, Moore S, Dvinge H, Kurz E, Theilgaard-Mönch K, Månsson R, Pedersen TA, Pabst T, Schrock E, Porse BT, Jacobsen SE, Bertone P, Tenen DG, Nerlov C. Modeling of C/EBPalpha mutant acute myeloid leukemia reveals a common expression signature of committed myeloid leukemia-initiating cells. Cancer Cell. 2008;13:299–310.

    Article  CAS  PubMed  Google Scholar 

  12. Snaddon J, Smith ML, Neat M, Cambal-Parrales M, Dixon-McIver A, Arch R, Amess JA, Rohatiner AZ, Lister TA, Fitzgibbon J. Mutations of CEBPA in acute myeloid leukemia FAB types M1 and M2. Gene Chromosomes Cancer. 2003;37:72–8.

    Article  CAS  Google Scholar 

  13. Gombart AF, Hofmann WK, 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 leukemias. Blood. 2002;99:1332–40.

    Article  CAS  PubMed  Google Scholar 

  14. Barjesteh van Waalwijk van Doorn-Khosrovani S, Erpelinck C, Meijer J, van Oosterhoud S, van Putten WL, Valk PJ, Berna Beverloo H, Tenen DG, Löwenberg B, Delwel R. Biallelic mutations in the CEBPA gene and low CEBPA expression levels as prognostic markers in intermediate-risk AML. Hematology J. 2003;4:31–40.

    Article  Google Scholar 

  15. Quintana-Bustamante O, Lan-Lan Smith S, Griessinger E, Reyal Y, Vargaftig J, Lister TA, Fitzgibbon J, Bonnet D. Overexpression of wild-type or mutants forms of CEBPA alters normal human hematopoiesis. Leukemia. 2012;26:1537–46.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Chim CS, Wong AS, Kwong YL. Infrequent hypermethylation of CEBPA promotor in acute myeloid leukaemia. Br J Haematol. 2002;119:988–90.

    Article  CAS  PubMed  Google Scholar 

  17. Griffiths EA, Gore SD, Hooker CM, Mohammad HP, McDevitt MA, Smith BD, Karp JE, Herman JG, Carraway HE. Epigenetic differences in cytogenetically normal versus abnormal acute myeloid leukemia. Epigenetics. 2010;5:590–600.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Lu Y, Chen W, Chen W, Stein A, Weiss LM, Huang Q. C/EBPA gene mutation and C/EBPA promoter hypermethylation in acute myeloid leukemia with normal cytogenetics. Am J Hematol. 2010;85:426–30.

    CAS  PubMed  Google Scholar 

  19. Hollink IH, van den Heuvel-Eibrink MM, Arentsen-Peters ST, Zimmermann M, Peeters JK, Valk PJ, Balgobind BV, Sonneveld E, Kaspers GJ, de Bont ES, Trka J, Baruchel A, Creutzig U, Pieters R, Reinhardt D, Zwaan CM. Characterization of CEBPA mutations and promoter hypermethylation in pediatric acute myeloid leukemia. Haematologica. 2011;96:384–92.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Lin TC, Hou HA, Chou WC, Ou DL, Yu SL, Tien HF, Lin LI. CEBPA methylation as a prognostic biomarker in patients with de novo acute myeloid leukemia. Leukemia. 2011;25:32–40.

    Article  CAS  PubMed  Google Scholar 

  21. Santana-Lemos BA, de Lima Lange AP, de Lira Benício MT, José TD, Lucena-Araújo AR, Krause A, Thomé CH, Rego EM. The CEBPA gene is down-regulated in acute promyelocytic leukemia and its upstream promoter, but not the core promoter, is highly methylated. Haematologica. 2011;96:617–20.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Szankasi P, Ho AK, Bahler DW, Efimova O, Kelley TW. Combined testing for CCAAT/enhancer-binding protein alpha (CEBPA) mutations and promoter methylation in acute myeloid leukemia demonstrates shared phenotypic features. Leuk Res. 2011;35:200–7.

    Article  CAS  PubMed  Google Scholar 

  23. Alberich-Jordà M, Wouters B, Balastik M, Shapiro-Koss C, Zhang H, Di Ruscio A, Radomska HS, Ebralidze AK, Amabile G, Ye M, Zhang J, Lowers I, Avellino R, Melnick A, Figueroa ME, Valk PJ, Delwel R, Tenen DG. C/EBPgamma deregulation results in differentiation arrest in acute myeloid leukemia. J Clin Invest. 2012;122:4490–504.

    Article  PubMed Central  PubMed  Google Scholar 

  24. Fasan A, Alpermann T, Haferlach C, Grossmann V, Roller A, Kohlmann A, Eder C, Kern W, Haferlach T, Schnittger S. Frequency and prognostic impact of CEBPA proximal, distal and core promoter methylation in normal karyotype AML: a study on 623 cases. PLoS One. 2013;8:e54365.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Vardiman JW, Thiele J, Arber DA, Brunning RD, Borowitz MJ, Porwit A, Harris NL, Le Beau MM, Hellström-Lindberg E, Tefferi A, Bloomfield CD. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood. 2009;114:937–51.

    Article  CAS  PubMed  Google Scholar 

  26. Lin J, Chen Q, Yang J, Qian J, Deng ZQ, Qian W, Chen XX, Ma JC, Xiong DS, Ma YJ, An C, Tang CY. DDX43 promoter is frequently hypomethylated and may predict a favorable outcome in acute myeloid leukemia. Leuk Res. 2014;38:601–7.

    Article  CAS  PubMed  Google Scholar 

  27. Hackanson B, Bennett KL, Brena RM, Jiang J, Claus R, Chen SS, Blagitko-Dorfs N, Maharry K, Whitman SP, Schmittgen TD, Lübbert M, Marcucci G, Bloomfield CD, Plass C. Epigenetic modification of CCAAT/enhancer binding protein alpha expression in acute myeloid leukemia. Cancer Res. 2008;68:3142–51.

    Article  CAS  PubMed  Google Scholar 

  28. Chen Q, Lin J, Yao DM, Qian J, Qian W, Yang J, Chai HY, Ma JC, Deng ZQ, Wang CZ, Li Y. Aberrant hypomethylation of DDX43 promoter in myelodysplastic syndrome. Br J Haematol. 2012;158:293–6.

    Article  CAS  PubMed  Google Scholar 

  29. Lin J, Yao DM, Qian J, Chen Q, Qian W, Li Y, Yang J, Wang CZ, Chai HY, Qian Z, Xiao GF, Xu WR. Recurrent DNMT3A R882 mutations in Chinese patients with acute myeloid leukemia and myelodysplastic syndrome. PLoS One. 2011;6:e26906.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Lin J, Yao DM, Qian J, Chen Q, Qian W, Li Y, Yang J, Wang CZ, Chai HY, Qian Z, Xiao GF, Xu WR. IDH1 and IDH2 mutation analysis in Chinese patients with acute myeloid leukemia and myelodysplastic syndrome. Ann Hematol. 2012;91:519–25.

    Article  CAS  PubMed  Google Scholar 

  31. Cilloni D, Carturan S, Gottardi E, Messa F, Messa E, Fava M, Diverio D, Guerrasio A, Lo-Coco F, Saglio G. Down-modulation of the C/EBPalpha transcription factor in core binding factor acute myeloid leukemias. Blood. 2003;102:2705–6.

    Article  CAS  PubMed  Google Scholar 

  32. Grossmann V, Bacher U, Kohlmann A, Butschalowski K, Roller A, Jeromin S, Dicker F, Kern W, Schnittger S, Haferlach T, Haferlach C. Expression of CEBPA is reduced in RUNX1-mutated acute myeloid leukemia. Blood Cancer J. 2012;2:e86.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Valent P, Horny HP, Bennett JM, Fonatsch C, Germing U, Greenberg P, Haferlach T, Haase D, Kolb HJ, Krieger O, Loken M, van de Loosdrecht A, Ogata K, Orfao A, Pfeilstöcker M, Rüter B, Sperr WR, Stauder R, Wells DA. Definitions and standards in the diagnosis and treatment of the myelodysplastic syndromes: consensus statements and report from a working conference. Leuk Res. 2007;31:727–36.

    Article  PubMed  Google Scholar 

  34. Jiang H, Xue Y, Wang Q, Pan J, Wu Y, Zhang J, Bai S, Wang Q, He G, Sun A, Wu D, Chen S. The utility of fluorescence in situ hybridization analysis in diagnosing myelodysplastic syndromes is limited to cases with karyotype failure. Leuk Res. 2012;36:448–52.

    Article  CAS  PubMed  Google Scholar 

  35. Wouters BJ, Löwenberg B, Erpelinck-Verschueren CA, van Putten WL, Valk PJ, Delwel R. Double CEBPA mutations, but not single CEBPA mutations, define a subgroup of acute myeloid leukemia with a distinctive gene expression profile that is uniquely associated with a favorable outcome. Blood. 2009;113:3088–91.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Pabst T, Eyholzer M, Fos J, Mueller BU. Heterogeneity within AML with CEBPA mutations; only CEBPA double mutations, but not single CEBPA mutations are associated with favourable prognosis. Br J Cancer. 2009;100:1343–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Dufour A, Schneider F, Metzeler KH, Hoster E, Schneider S, Zellmeier E, Benthaus T, Sauerland MC, Berdel WE, Büchner T, Wörmann B, Braess J, Hiddemann W, Bohlander SK, Spiekermann K. Acute myeloid leukemia with biallelic CEBPA gene mutations and normal karyotype represents a distinct genetic entity associated with a favorable clinical outcome. J Clin Oncol. 2010;28:570–7.

    Article  CAS  PubMed  Google Scholar 

  38. Taskesen E, Bullinger L, Corbacioglu A, Sanders MA, Erpelinck CA, Wouters BJ, van der van der Poel-van de Luytgaarde SC, Damm F, Krauter J, Ganser A, Schlenk RF, Löwenberg B, Delwel R, Döhner H, Valk PJ, Döhner K. Prognostic impact, concurrent genetic mutations, and gene expression features of AML with CEBPA mutations in a cohort of 1182 cytogenetically normal AML patients: further evidence for CEBPA double mutant AML as a distinctive disease entity. Blood. 2011;117:2469–75.

    Article  CAS  PubMed  Google Scholar 

  39. Kaeferstein A, Krug U, Tiesmeier J, Aivado M, Faulhaber M, Stadler M, Krauter J, Germing U, Hofmann WK, Koeffler HP, Ganser A, Verbeek W. The emergence of a C/EBPalpha mutation in the clonal evolution of MDS towards secondary AML. Leukemia. 2003;17:343–9.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This study was supported by National Natural Science foundation of China (81270630, 81172592), Science and Technology Special Project in Clinical Medicine of Jiangsu Province (BL2012056), 333 Project of Jiangsu Province (BRA2013136), Jiangsu Government Scholarship for Overseas Studies, Social Development Foundation of Zhenjiang (SH2013042, SH2013082, SH2014044), Research and Development Foundation of Clinical Medicine of Jiangsu University (JLY20120013, JLY20120011), Key Medical Talent Program of Zhenjiang, and Science and Technology Infrastructure Program of Zhenjiang (SS2012003).

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The authors stated that there are no conflicts of interest regarding the publication of this article.

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    Authors and Affiliations

    1. Department of Hematology, Affiliated People’s Hospital of Jiangsu University, 8 Dianli Rd., Zhenjiang, 212002, Jiangsu, People’s Republic of China

      Xiang-mei Wen, Jing Yang, Ying-ying Zhang, Xiao-wen Zhu, Hong Guo & Jun Qian

    2. Laboratory Center, Affiliated People’s Hospital of Jiangsu University, 8 Dianli Rd., Zhenjiang, 212002, Jiangsu, People’s Republic of China

      Wei Qian, Dong-ming Yao, Zhao-qun Deng & Jiang Lin

    3. School of Medical Science and Laboratory Medicine, Jiangsu University, Zhenjiang, 212013, Jiangsu, People’s Republic of China

      Jia-bo Hu

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    Wen, Xm., Hu, Jb., Yang, J. et al. CEBPA methylation and mutation in myelodysplastic syndrome. Med Oncol 32, 192 (2015). https://doi.org/10.1007/s12032-015-0605-z

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