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 5′UTR 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.
Highlights
The p53 pathway is well known as a central player in the cellular stress response and tumor suppression
We demonstrate that lower Apoptosis Stimulating Protein of p53-2 (ASPP2) mRNA and protein expression levels are statistically significantly associated with clinical unfavorable disease and early chemotherapyinduction failure in de novo as well as secondary acute myeloid and lymphoid leukemia
ASPP2 mRNA expression is significantly attenuated in acute leukemia patients
Summary
The p53 pathway is well known as a central player in the cellular stress response and tumor suppression. In some hematopoietic malignancies, inactivating mutations of p53 are involved with chromosomal instability and progression towards acute leukemia, such as complex karyotype myelodysplastic syndromes[3,4,5,6] and chronic phase Philadelphia-chromosome positive chronic myeloid leukemia (CML)[7]. Chromosomal aberrations of the long arm of chromosome 17 (locus of p53) or inactivating p53 mutations impede cancer therapies, such as fludarabine-based chemotherapy in CLL[8], BCR/ABL-targeted therapies in CML[9] – as well as induction chemotherapy in AML[10]. In most cases of de novo acute leukemia, p53 mutations or chromosomal aberrations of chromosome 17 are uncommon, but primarily associate with therapy-related acute myeloid leukemias[11] and MDS-related complex karyotype leukemia[10,12,13]. The molecular mechanisms that inactivate the p53 pathway in acute leukemia remain unclear
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