MEK/ERK and PI3K/AKT pathway inhibitors affect the transformation of myelodysplastic syndrome into acute myeloid leukemia via H3K27me3 methylases and de ‑methylases

Int J Oncol. 2023 Dec;63(6):140. doi: 10.3892/ijo.2023.5588. Epub 2023 Nov 3.ABSTRACTThe transformation of myelodysplastic syndrome (MDS) into acute myeloid leukemia (AML) poses a significant clinical challenge. The trimethylation of H3 on lysine 27 (H3K27me3) methylase and de‑methylase pathway is involved in the regulation of MDS progression. The present study investigated the functional mechanisms of the MEK/ERK and PI3K/AKT pathways in the MDS‑to‑AML transformation. MDS‑AML mouse and SKM‑1 cell models were first established and this was followed by treatment with the MEK/ERK pathway inhibitor, U0126, the PI3K/AKT pathway inhibitor, Ly294002, or their combination. H3K27me3 methylase, enhancer of zeste homolog (EZH)1, EZH2, demethylase Jumonji domain‑containing protein‑3 (JMJD3) and ubiquitously transcribed tetratricopeptide repeat on chromosome X (UTX) and H3K27me3 protein levels were determined using western blot analysis. Cell viability, cycle distribution and proliferation were assessed using CCK‑8, flow cytometry, EdU and colony formation assays. The ERK and AKT phosphorylation levels in clinical samples and established models were determined, and SKM‑1 cell behaviors were assessed. The levels of H3K27me3 methylases and de‑methylases and distal‑less homeobox 5 (DLX5) were measured. The results revealed that the ERK and AKT phosphorylation levels were elevated in patients with MDS and MDS‑AML, and in mouse models. Treatment with U0126, a MEK/ERK p...
Source: International Journal of Oncology - Category: Cancer & Oncology Authors: Source Type: research