Attenuated Expression of Apoptosis Stimulating Protein of p53-2 (ASPP2) in Human Acute Leukemia Is Associated with Therapy Failure

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.

Expression and significance of ASPP2 in squamous carcinoma of esophagus

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DNA methylation in silkworm genome may provide insights into epigenetic regulation of response to Bombyx mori cypovirus infection

“…P53 is a central apoptotic regulator 45 , and ASPP2 is a damage-inducible p53-binding protein that enhances apoptosis through p53-dependent and p53-independent pathways 46 . Attenuation of ASPP2 is caused by hypermethylation of the promoter and 5′ UTR regions in native leukemia blasts 47 . The hypermethylation and down-regulation of ASPP2 in BmCPV infected midgut suggests that BmCPV infection may lead to hypermethylation of ASPP2, which in turn may suppress the expression of ASPP2 and facilitate the proliferation of infected cells.…”

Synergistic inhibitory effects on hepatocellular carcinoma with recombinant human adenovirus Aspp2 and oxaliplatin via p53-independent pathway in vitro and in vivo

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