Gene and protein analysis reveals that p53 pathway is functionally inactivated in cytogenetically normal Acute Myeloid Leukemia and Acute Promyelocytic Leukemia

Abstract

BackgroundMechanisms that inactivate the p53 pathway in Acute Myeloid Leukemia (AML), other than rare mutations, are still not well understood.MethodsWe performed a bioinformatics study of the p53 pathway function at the gene expression level on our collection of 1153 p53-pathway related genes. Publically available Affymetrix data of 607 de-novo AML patients at diagnosis were analyzed according to the patients cytogenetic, FAB and molecular mutations subtypes. We further investigated the functional status of the p53 pathway in cytogenetically normal AML (CN-AML) and Acute Promyelocytic Leukemia (APL) patients using bioinformatics, Real-Time PCR and immunohistochemistry.ResultsWe revealed significant and differential alterations of p53 pathway-related gene expression in most of the AML subtypes. We found that p53 pathway-related gene expression was not correlated with the accepted grouping of AML subtypes such as by cytogenetically-based prognosis, morphological stage or by the type of molecular mutation. Our bioinformatic analysis revealed that p53 is not functional in CN-AML and APL blasts at inducing its most important functional outcomes: cell cycle arrest, apoptosis, DNA repair and oxidative stress defense. We revealed transcriptional downregulation of important p53 acetyltransferases in both CN-AML and APL, accompanied by increased Mdmx protein expression and inadequate Chk2 protein activation.ConclusionsOur bioinformatic analysis demonstrated that p53 pathway is differentially inactivated in different AML subtypes. Focused gene and protein analysis of p53 pathway in CN-AML and APL patients imply that functional inactivation of p53 protein can be attributed to its impaired acetylation. Our analysis indicates the need in further accurate evaluation of p53 pathway functioning and regulation in distinct subtypes of AML.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-017-0249-2) contains supplementary material, which is available to authorized users.

Reduced murine double minute 2 and 4 protein, but not messenger RNA, expression is associated with more severe disease in myelodysplastic syndromes and acute myeloblastic leukaemia

“…Previous studies have suggested that MDM4 mRNA levels are overexpressed in AML, 22,23 while variable results have been observed for mRNA expression levels of MDM2 and p53 in myeloid malignancies 19,21,22,25,31 . We found no significant difference in mRNA expression of MDM2 , p53 and MDM4 between AML, MDS and CMML samples and control samples.…”

“…20 The same discrepancies were observed for MDM4 and p53 protein expression and appeared to be largely due to the techniques, and possibly control samples used (Table 1). [17][18][19][20][21][22][23][24][25][26][27][28][30][31][32][33] After studies suggesting overexpression of MDM2 and MDM4, clinical trials have been conducted in AML with MDM2 inhibitors generally combined with chemotherapy, including idasanutlin with so far limited results 34 and HDM201 with very preliminary ones 35 or combined with other molecules i.e., milademetan with quizartinib 36 or azacitidine. 37 MDM4 inhibitors have also been tested in AML in vitro, with very limited in vivo experience.…”

The Pan-Sirtuin Inhibitor MC2494 Regulates Mitochondrial Function in a Leukemia Cell Line

“…Elevated sirtuins expression has been reported in AML and in other cancers (34) and promotes tumourigenesis and drug resistance (6). Particularly, SIRT1 deacetylates different histone and nonhistone proteins, among them p53, regulating both cell cycle and mitochondrial function (35) and playing a critical role in tumor initiation progression and metastasis (30,36,37). Effects of p53 on regulation of PGC1α, a metabolic modulator in cancer (38,39) have been previously reported (40,41), with p53-mediated PGC1α up-regulation orchestrating antioxidant and metabolic response (42).…”

Involvement of the PI3K/AKT Intracellular Signaling Pathway in the AntiCancer Activity of Hydroxytyrosol, a Polyphenol from Olea europaea, in Hematological Cells and Implication of HSP60 Levels in Its Anti-Inflammatory Activity

“…Normally, in the case of DNA damage and excessive cellular stress, its expression levels and activation increase in order to stop the cell cycle, allowing DNA repair or entry into apoptosis [48]. However, p53 is mutated or silenced in 50-55% of human cancers [49] and, therefore, it is one of the most widely studied targets in the search for new anticancer compounds. In the present study, in the two cell lines used, p53 was not functional since it presented a nonsense mutation according to the Cancer Cell Line Encyclopedia of the Broad Institute.…”