TP53 GENE EXPRESSION IS INCREASED AND CORRELATES WITH RHOC IN PATIENTS WITH ACUTE MYELOID LEUKEMIA

Abstract

Background: Mutations in the tumor suppressor gene TP53 are found in approximately 10% of acute myeloid leukemia (AML) cases and are associated with a worse prognosis. Deregulation of the p53 signaling pathway occurs by other mechanisms in additional AML patients. Therefore, the investigation of new genes associated with p53 pathway is important to understand the physiopathology of TP53 -mutated and TP53 -wild type AML. In this context, RHO GTPases have been shown to participate in p53 signaling, but this relation has not been explored in AML. Objectives: In this study, we aimed to evaluate the expression of TP53 and its regulators (MDM2 and CDKN2A) in patients with de novo AML, and AML with myelodysplasia related changes (AML-MRC). We also investigated the correlation among TP53, MDM2, CDKN2A, RHOA, RHOB, and RHOC gene expressions. Material and methods: Gene expression was evaluated by quantitative PCR in bone marrow samples from healthy donors (n = 11) and patients with AML (n = 33), and AML-MRC (n = 15). This study was approved by the Institutional Ethics Committees. Groups were compared with the Mann-Whitney test. Correlations were performed with Spearman test. Results: TP53 expression was increased in both de novo AML (p = 0.0022) and AML-MRC patients (P = 0.0008) compared to healthy donors. A decrease in MDM2 gene expression was observed in de novo AML (P = 0.0101) and AML-MRC (p = 0.0422). Confirming our previous results, RHOC expression was also increased in both groups of AML patients (p = 0.0025 and p = 0.0129), whereas RHOA expression was decreased in AML-MRC patients (p = 0.0374). CDKN2A and RHOB expressions did not significantly differ among the groups. Additionally, TP53 expression positively correlated with RHOA (r = 0.2949, p = 0.0338) and RHOC (r = 0.3373, p = 0.0145). Conclusions: TP53 and RHOC gene expressions are increased and positively correlated in de novo AML and AML-MRC. The increase in TP53 expression may be a compensatory mechanism to suppress disease progression. Moreover, a complex feedback mechanism between p53 and MDM2 could be responsible for the low expression of MDM2. Correlation between TP53 and RHOC expression suggest a possible relation between these signaling pathways in AML. Funding: Funded by FAPESP.