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Fas expression at diagnosis as a biomarker of azacitidine activity in high-risk MDS and secondary AML

Leukemia volume 26, pages 2297–2299 (2012)Cite this article

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In advanced myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia (sAML), aberrant methylation targets genes involved in apoptosis, cell cycle, DNA repair or adherence, or silencing tumor suppressor genes.1, 2, 3 The correlation between DNA hypermethylation and disease progression provides a rationale for the therapeutic use of Dnmt inhibitors. Azacitidine induces a hematological response in 40–50% of high-risk (HR)-MDS patients, delays the disease progression to sAML and significantly prolongs overall survival.4 FAS/TNFRSF6/APO1 that belongs to a set of genes involved in the control of apoptosis is hypermethylated in tumors.5, 6, 7 We have previously shown that Fas is overexpressed in low/int-1-risk (LR)-MDS.8 Conversely, decreased expression of pro-apoptotic Fas, or Fas-associated via death domain (FADD) or increased anti-apoptotic Bcl2 protein in int-2 or HR-MDS could participate in resistance to apoptosis and contribute to disease progression.

We then investigated whether the FAS gene expression was epigenetically regulated along the MDS disease progression to AML. Variations of the methylation level at FAS promoter have already been described in one CpG island located over the transcription start site (+1) and in a 5′-regulatory region located upstream the CpG island in the NIH3T3 cell line transformed by KRAS or in primary tumor cells.5, 6, 7, 9 Thus, we extensively studied DNA methylation of the promoter region spanning between −899 and +231, which contains 35 CpG dinucleotides, of which 26 belong to a CpG island. The FAS promoter was amplified from bisulfite-treated genomic DNA extracted from CD34+ cells in 18 LR-MDS, 8 HR-MDS, 11 sAML and 8 controls (Supplementary Table S2 for primers). The PCR products were cloned in bacteria, and at least eight clones per case were sequenced. Global level of methylation expressed as the percentage of methylated CpG at each dinucleotide was significantly higher in sAML compared with LR-MDS (P=0.01), HR-MDS (P=0.008), and LR- or HR-MDS (P=0.004). The most heavily and differentially methylated CpGs 1–8 were located in the 5′-region upstream of the CpG island (Figure 1b). The Fas RFI was inversely correlated with the percentage of methylated CpG1-8 (Figure 1c). These results indicate that the FAS promoter region was overmethylated in sAML compared with LR- or HR-MDS cells, consistent with the loss of Fas protein expression.

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Acknowledgements

This work was supported by grants from the Direction régionale de la recherche clinique AP-HP (PHRC MAD-06). SE was recipient of a grant from the Canceropole Ile-de-France and from the Société Française d’Hématologie (SFH); CH and BB were recipients of a grant from Fondation pour la Recherche Médicale. We are undebted to Professor B Quesnel, Lille; Professor O Beyne-Rauzy, Toulouse; Professor M Hunault-Berger Angers, Dr S Park, Paris Cochin; Dr B Slama, Avignon; for recording patients.

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Authors and Affiliations

  1. Département d’Immunologie-Hématologie, Institut Cochin, Paris, France

    S Ettou, C Humbrecht, B Benet, V Bardet, C Lacombe, F Dreyfus, P Mayeux & M Fontenay

  2. INSERM U1016, Paris, France

    S Ettou, C Humbrecht, B Benet, V Bardet, C Lacombe, F Dreyfus, P Mayeux & M Fontenay

  3. Centre National de la Recherche Scientifique, Unité mixte de recherche 8104, Paris, France

    S Ettou, C Humbrecht, B Benet, V Bardet, C Lacombe, F Dreyfus, P Mayeux & M Fontenay

  4. Faculté de médecine, Université Paris Descartes, Paris, France

    S Ettou, E Audureau, C Humbrecht, B Benet, V Bardet, C Lacombe, F Dreyfus, P Mayeux & M Fontenay

  5. Département d’Epidémiologie et de Biostatistiques, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Paris, France

    E Audureau

  6. Departement de biologie du développement et de la reproduction, UMR INRA-ENVA, Domaine de Vilvert, Jouy en Josas, France

    H Jammes

  7. Faculté de Médecine, Université Paris Sud-XI, Le Kremlin-Bicêtre, France

    T Clozel & E Solary

  8. Assistance Publique-Hôpitaux de Paris, Hôpital Broca-Cochin-Hôtel-Dieu, Service d’hématologie biologique, Paris, France

    V Bardet, C Lacombe & M Fontenay

  9. Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Unité fonctionnelle d’hématologie, Paris, France

    F Dreyfus

  10. INSERM 1009, Institut Gustave Roussy, Villejuif, France

    E Solary

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Correspondence to M Fontenay.

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Author contributions

SE, CH and BB performed research; EA, VB, TC, CL, PM and FD analyzed data; HJ contributed analytical tools and analyzed data; ES and MF analyzed data and wrote the manuscript.

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Ettou, S., Audureau, E., Humbrecht, C. et al. Fas expression at diagnosis as a biomarker of azacitidine activity in high-risk MDS and secondary AML. Leukemia 26, 2297–2299 (2012). https://doi.org/10.1038/leu.2012.152

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