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GADD45A methylation predicts poor overall survival in acute myeloid leukemia and is associated with IDH1/2 and DNMT3A mutations

Leukemia volume 27, pages 1588–1592 (2013)Cite this article

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Acute myeloid leukemia (AML) is a heterogeneous disease with variable treatment outcome. Despite recent advances in understanding the key molecular mechanisms of myeloid leukemogenesis, risk stratification remains imperfect, particularly in the intermediate risk group in which a large proportion of patients have a normal karyotype. For this group of patients, genetic alterations in genes, such as FLT3, NPM1 and CEPBA, provide useful prognostic information, but alone are not sufficient to accurately predict prognosis for all patients. Recently, recurrent mutations in epigenetic modifiers such as IDH1/2,1 DNMT3A,2 and TET23 have been described, but their prognostic significance remains somewhat controversial, and it is unclear if targeted therapies will evolve from identification of these mutations.4 Identification of target genes that undergo epigenetic modification in the landscape of somatic mutations in epigenetic modifiers is likely to yield important prognostic information, and potentially identify novel biomarkers of response to demethylating agents, which are currently showing promise in the treatment of AML.

Growth arrest and DNA-damage inducible alpha (GADD45A) is a tumour suppressor gene that has cell-type specific roles in cellular stress, coordinating DNA repair and de-methylation, cell cycle arrest and pro-apoptotic or pro-survival responses.5, 6 Although downregulation of GADD45A has been linked to the presence of FLT3-ITD and FLT3-TKD mutants,7 and recently with RUNX1 c-terminal mutations,8 there is a broad downregulation of GADD45A in AML and other mechanisms associated with this remain to be determined. Previous studies in solid tumours have identified atypical methylation of GADD45A at four discrete CpG residues (CpG1-4) ∼700 bp upstream of the transcriptional start site, which correlates with gene expression and has been linked to tumour response in vitro and in xenograft models.7, 9, 10, 11 Here, we assessed DNA methylation of these same key CpG residues in GADD45A in AML and determined co-occurrence with other recurrent mutations and impact on patient outcome.

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Acknowledgements

The authors would like to acknowledge G Engler and L McMillan for preparation and mutation screening of patient samples. The authors also acknowledge funding obtained from the National Health and Medical Research Council and the Shahin Research Fellowship. We also acknowledge statistical assistance provided by the Data Management and Analysis Centre, Discipline of Public Health, University of Adelaide and J Muirhead and E Paul from the School of Public Health and Preventative Medicine, Alfred Centre, Victoria.

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Authors and Affiliations

  1. Department of Haematology, Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia

    M Perugini, D G Iarossi, C H Kok, S M Diakiw, A L Brown, L Bik To, I D Lewis & R J D'Andrea

  2. Department of Haematology, Royal Adelaide Hospital, Adelaide, South Australia, Australia

    M Perugini, S Danner, L Bik To & I D Lewis

  3. Centre for Personalised Cancer Medicine and School of Medicine, the University of Adelaide, Adelaide, South Australia, Australia

    M Perugini, C H Kok, L Bik To, I D Lewis & R J D'Andrea

  4. Department of Clinical Haematology, The Alfred Hospital and Monash University, Commercial Road, Melbourne, Victoria, Australia

    N Cummings & A H Wei

  5. Schools of Molecular and Biomedical Sciences, the University of Adelaide, Adelaide, South Australia, Australia

    A L Brown & R J D'Andrea

  6. Department of Haematology and Oncology and Basil Hetzel Institute for Translational Health Research, the Queen Elizabeth Hospital, Adelaide, South Australia, Australia

    P Bardy & R J D'Andrea

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  1. M Perugini
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Correspondence to R J D'Andrea.

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Competing interests

AH Wei receives clinical trial funding from Celgene. The remaining authors declare no conflict of interest.

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Perugini, M., Iarossi, D., Kok, C. et al. GADD45A methylation predicts poor overall survival in acute myeloid leukemia and is associated with IDH1/2 and DNMT3A mutations. Leukemia 27, 1588–1592 (2013). https://doi.org/10.1038/leu.2012.346

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