Gene Expression Profiles Identify Biomarkers of Resistance to Decitabine in Myelodysplastic Syndromes

Abstract

Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disease characterized by inefficient hematopoiesis and the potential development of acute leukemia. Among the most notable advances in the treatment of MDS is the hypomethylating agent, decitabine (5-aza-2′deoxycytidine). Although decitabine is well known as an effective method for treating MDS patients, only a subset of patients respond and a tolerance often develops, leading to treatment failure. Moreover, decitabine treatment is costly and causes unnecessary toxicity. Therefore, clarifying the mechanism of decitabine resistance is important for improving its therapeutic efficacy. To this end, we established a decitabine-resistant F-36P cell line from the parental F-36P leukemia cell line, and applied a genetic approach employing next-generation sequencing, various experimental techniques, and bioinformatics tools to determine differences in gene expression and relationships among genes. Thirty-eight candidate genes encoding proteins involved in decitabine-resistant-related pathways, including immune checkpoints, the regulation of myeloid cell differentiation, and PI3K-Akt signaling, were identified. Interestingly, two of the candidate genes, AKT3 and FOS, were overexpressed in MDS patients with poor prognoses. On the basis of these results, we are pursuing development of a gene chip for diagnosing decitabine resistance in MDS patients, with the goal of ultimately improving the power to predict treatment strategies and the prognosis of MDS patients.

Transfer of miR‐4755‐5p through extracellular vesicles and particles induces decitabine resistance in recipient cells by targeting CDKN2B

“…Qin et al established a DAC‐resistant acute promyelocytic leukemia cell line (HL60R) and found that dCK protein expression was markedly reduced in HL60R 3 . A leukemia decitabine‐resistant F‐36P cell line was established from the parental F‐36P cell line, gene sequencing analysis indicated AKT3 and FOS genes are overexpressed in decitabine‐resistant cells, suggesting these candidate genes may correlate with MDS prognoses 25 . In this study, we established a DAC‐resistant KG1a cell line (KG1a‐DAC) and found that co‐incubation with KG1a‐DAC can confer DAC resistance in KG1a.…”