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.
Highlights
Myelodysplastic syndrome (MDS) is a hematologic disorder characterized by marrow failure and a risk of clonal progression
We further found that F-36P/DEC cells stably proliferated over 72 h (Figure 1C)
To further explore the biological properties of F-36P/DEC cells, we compared the cell-cycle properties of F-36P/DEC cells with those of F-36P cells, finding that the proportion of cells in the G2/M phase of the cell cycle was significantly increased in F-36P/DEC cells (Figure 1E)
Summary
Myelodysplastic syndrome (MDS) is a hematologic disorder characterized by marrow failure and a risk of clonal progression. MDS, known as pre-leukemia, is characterized by a high risk of transformation to acute myeloid leukemia (AML). Allogeneic HSCT can be a curative treatment option for MDS, high treatment-related mortality limits the universal application of allogeneic HSCT in all patients with MDS. This has led to the development of the International Prognostic Scoring System (IPSS), a risk stratification strategy for predicting prognosis and selecting appropriate patients who might benefit from allogeneic HSCT
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