Effects of decitabine on megakaryocyte maturation in patients with myelodysplastic syndromes

Abstract

Thrombocytopenia is a common, often fatal complication experienced by patients with myelodysplastic syndromes (MDS). 5-aza-2′-deoxycytidine (decitabine) has been used to treat MDS patients with thrombocytopenia with a response rate of 45–50%. However, the mechanism of its effects on megakaryocytes remains unclear. In the present study, the effect of decitabine on megakaryocyte maturation was investigated. A total of 20 MDS patients diagnosed with thrombocytopenia were enrolled, including 16 refractory anemia with excess blasts (RAEB)-1 patients and 4 RAEB-2 patients], in addition to 20 leukemia patients that had achieved complete remission and 20 healthy donors. Overall, 65% of MDS patients exhibited a response to decitabine, with an increase in platelet count identified in 80% of patients. In the MDS group, the mean platelet count was significantly increased following one cycle of decitabine chemotherapy (36.85±24.54 vs. 84.90±61; P=0.001); however, no significant difference in megakaryocyte number was identified prior to and following treatment. Additionally, bone marrow mononuclear cells of the MDS patients were cultured in vitro with various concentrations of decitabine (0.0, 2.0, 2.5, 3.0 µM), and cluster of differentiation (CD)41 levels were examined via flow cytometry. The MDS and normal control groups exhibited the highest levels of CD41 expression following treatment with 2.0 µM decitabine (mean fluorescence intensity, 294.07±47.34 and 258.95±28.05, respectively). In conclusion, these results indicate that the DNA-hypomethylating agent, decitabine, may induce the differentiation and maturation of myelodysplastic megakaryocytes in MDS patients, even at low concentrations. Thus, the repeated administration of decitabine at lower doses in MDS patients may be useful in clinical practice, and may lead to the development of alternative treatments for other diseases of abnormal megakaryocyte differentiation, such as idiopathic thrombocytopenic purpura, however, future studies are required to investigate this.

Decitabine prior to salvaged cord blood transplantation for acute myeloid leukaemia/myelodysplastic syndrome not in remission

“…Decitabine also improves expression of FOXP3 gene to stimulate regulatory T cells to inhibit aGVHD 19 . Moreover, decitabine may increase platelet counts by enhancing platelet release and megakaryocyte maturation 20 . In our study, we found that decitabine group and higher TNC and CD34 counts were associated with short median time of platelet engraftment in univariate analysis.…”

Phenotype of mesenchymal stem cells from patients with myelodyplastic syndrome maybe partly modulated by decitabine

“…A previous study revealed that a concentration of decitabine <10 µM did not inhibit the proliferation of MDS-MSCs, and 0.25 µM decitabine induced the immune response and enhanced the sensitivity of tumor cells to immune cells in vitro (21). Decitabine is generally administered daily for 5 consecutive days in a clinical setting (22). Therefore, the current study analyzed the effect of decitabine on MDS-MSCs for 5 days.…”

Distinct bone marrow morphologic features discriminate myelodysplastic syndromes patients with and without an early platelet response to decitabine

“…An early increase in platelet counts (EPR) precedes the response of other parameters in DAC‐treated MDS patients, and is a predictive factor of overall as well as leukaemia‐free survival, 4‐6 EPR may be associated with increased differentiation of megakaryocytes (MK) and improved platelet shedding 7 , 8 . EPR may be independent of the number of MK prior to DAC application, 5 while an increased number of ‘platelet‐shedding’ MK 4 weeks after DAC treatment in patients with thrombocytopenia after allogeneic SCT has been observed 9 as well as increased MK maturation after DAC treatment 10 …”