Abstract
The molecular mechanisms responsible for the evolution from the preleukemic entities of low-risk myelodysplastic syndrome (MDS) to the less favorable forms of high-risk MDS, as well as those enabling transformation to acute myeloid leukemia (AML), are still incompletely understood. Abundant evidence from solid tumors demonstrates that preneoplastic lesions activate signaling pathways of a DNA damage response (DDR), which functions as an ‘anticancer barrier’ hindering tumorigenesis. Testing the hypothesis that subgroups of MDS and AML differ with respect to DDR, we first assessed markers of DDR (phosphorylation of ATM, Chk-1, Chk-2 and H2AX) in cell lines representing different entities of MDS (P39, MOLM-13) and AML (MV4-11, KG-1) before and after γ-irradiation. Although γ-irradiation induced apoptosis and G2/M arrest and a concomitant increase in the phosphorylation of ATM, Chk-1 and H2AX in MDS-derived cell lines, this radiation response was attenuated in the AML-derived cell lines. It is noteworthy that KG-1, but not P39 cells exhibit signs of an endogenous activation of the DDR. Similarly, we found that the frequency of P-ATM+ cells detectable in bone marrow (BM) biopsies increased in samples from patients with AML as compared with high-risk MDS samples and significantly correlated with the percentage of BM blasts. In contrast, the frequency of γ-H2AX+ cells was heterogeneous in all subgroups of AML and MDS. Whereas intermediate-1 MDS samples contained as little P-Chk-1 and P-Chk-2 as healthy controls, staining for both checkpoint kinases increased in intermediate-2 and high-risk MDS, yet declined to near-to-background levels in AML samples. Thus the activation of Chk-1 and Chk-2 behaves in accord with the paradigm established for solid tumors, whereas ATM is activated during and beyond transformation. In conclusion, we demonstrate the heterogeneity of the DDR response in MDS and AML and provide evidence for its selective suppression in AML because of the uncoupling between activated ATM and inactive checkpoint kinases.
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Acknowledgements
SB and LA contributed equally to this paper. SB receives a scholarship from the Deutsche Forschungsgemeinschaft, LA receives a scholarship from Assistance Publique-Hopitaux de Paris and Caisse Nationale d'Assurance Maladie des Professions Indépendantes. GK is supported by Cancéropôle Ile-de-France, Institut National du Cancer, Fondation de France, Association Laurette Fugain, Cent pour Sang la Vie, Agence National de la Recherche and the European Commission (ApoSys, ChemoRes., Apopt-Train, RIGHT). The project was carried out with the support from the Gutermuth-Stiftung. SB, LA, NT, LG, CF, MT and KAO. performed and analysed the experiments. WKH., SK., GB, OGO., MR, CG, VE, SdeB., ST and PF provided bone marrow biopsies and patient data. SB and GK designed the study and wrote the paper.
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Boehrer, S., Adès, L., Tajeddine, N. et al. Suppression of the DNA damage response in acute myeloid leukemia versus myelodysplastic syndrome. Oncogene 28, 2205–2218 (2009). https://doi.org/10.1038/onc.2009.69
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DOI: https://doi.org/10.1038/onc.2009.69