title: Suppression of the DNA damage response in acute myeloid leukemia versus myelodysplastic syndrome.
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 gamma-irradiation. Although gamma-irradiation induced apoptosis and G(2)/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 gamma-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.
authors.affiliation: INSERM U848, Institut Gustave Roussy, Pavillon de Recherche 1, 39 rue Camille Desmoulins, Villejuif, France.
authors.forename: S
authors.initials: S
authors.lastname: Boehrer
authors.forename: L
authors.initials: L
authors.lastname: Adès
authors.forename: N
authors.initials: N
authors.lastname: Tajeddine
authors.forename: W K
authors.initials: WK
authors.lastname: Hofmann
authors.forename: S
authors.initials: S
authors.lastname: Kriener
authors.forename: G
authors.initials: G
authors.lastname: Bug
authors.forename: O G
authors.initials: OG
authors.lastname: Ottmann
authors.forename: M
authors.initials: M
authors.lastname: Ruthardt
authors.forename: L
authors.initials: L
authors.lastname: Galluzzi
authors.forename: C
authors.initials: C
authors.lastname: Fouassier
authors.forename: M
authors.initials: M
authors.lastname: Tailler
authors.forename: K A
authors.initials: KA
authors.lastname: Olaussen
authors.forename: C
authors.initials: C
authors.lastname: Gardin
authors.forename: V
authors.initials: V
authors.lastname: Eclache
authors.forename: S
authors.initials: S
authors.lastname: de Botton
authors.forename: S
authors.initials: S
authors.lastname: Thepot
authors.forename: P
authors.initials: P
authors.lastname: Fenaux
authors.forename: G
authors.initials: G
authors.lastname: Kroemer
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D001706:Biopsy; D001853:Bone Marrow / Q000473:pathology; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D064447:Checkpoint Kinase 2; D004249:DNA Damage / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D042381:Granulocyte Precursor Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; D011838:Radiation-Sensitizing Agents; D025521:Tumor Suppressor Proteins; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases