Attenuated expression of apoptosis stimulating protein of p53-2 (ASPP2) in human acute leukemia is associated with therapy failure

Marcus M. Schittenhelm, Barbara Illing, Figen Ahmut, Katharina Henriette Rasp, Gunnar Blumenstock, Konstanze Döhner, Charles D. Lopez, Kerstin M. Kampa-Schittenhelm

    Research output: Contribution to journalArticle

    11 Scopus citations

    Abstract

    Inactivation of the p53 pathway is a universal event in human cancers and promotes tumorigenesis and resistance to chemotherapy. Inactivating p53 mutations are uncommon in non-complex karyotype leukemias, thus the p53-pathway must be inactivated by other mechanisms. The Apoptosis Stimulating Protein of p53-2 (ASPP2) is a damage-inducible p53-binding protein that enhances apoptosis at least in part through a p53-mediated pathway. We have previously shown, that ASPP2 is an independent haploinsufficient tumor suppressor in vivo. Now, we reveal that ASPP2 expression is significantly attenuated in acute myeloid and lymphoid leukemia - especially in patients with an unfavorable prognostic risk profile and patients who fail induction chemotherapy. In line, knock down of ASPP2 in expressing leukemia cell lines and native leukemic blasts attenuates damage-induced apoptosis. Furthermore, cultured blasts derived from high-risk leukemias fail to induce ASPP2 expression upon anthracycline treatment. The mechanisms of ASPP2 dysregulation are unknown. We provide evidence that attenuation of ASPP2 is caused by hypermethylation of the promoter and 59UTR regions in native leukemia blasts. Together, our results suggest that ASPP2 contributes to the biology of leukemia and expression should be further explored as a potential prognostic and/or predictive biomarker to monitor therapy responses in acute leukemia.

    Original languageEnglish (US)
    Article numbere80193
    JournalPloS one
    Volume8
    Issue number11
    DOIs
    StatePublished - Nov 27 2013

    ASJC Scopus subject areas

    • Biochemistry, Genetics and Molecular Biology(all)
    • Agricultural and Biological Sciences(all)
    • General

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  • Cite this

    Schittenhelm, M. M., Illing, B., Ahmut, F., Rasp, K. H., Blumenstock, G., Döhner, K., Lopez, C. D., & Kampa-Schittenhelm, K. M. (2013). Attenuated expression of apoptosis stimulating protein of p53-2 (ASPP2) in human acute leukemia is associated with therapy failure. PloS one, 8(11), [e80193]. https://doi.org/10.1371/journal.pone.0080193