Study On The Mechanism Of Decitabine Promoting Platelet Recovery In Myelodysplastic Syndromes/Acute Myeloid Leukemia Patients

Objective:To explore the underlying mechanism of decitabine(DAC)promoting platelet(PLT)recovery in myelodysplastic syndromes(MDS)/acute myeloid leukemia(AML)patients.Methods:Firstly,we retrospectively analyze the clinical data of MDS patients(n=37),AML patients(n=15)along with healthy donors(HD)(n=10)to detect the levels of cytokines in peripheral blood(PB)plasma,which including interleukin-1?(IL-1?)(pg/ml),IL-6(pg/ml),IL-2R(U/ml),IL-8(pg/ml)and IL-10(pg/ml).After statistical analysis of the differences between patients and healthy donors,the relationship between cytokine level and platelet level was further analyzed.In order to verify the consistency of the cytokine levels in bone marrow(BM)plasma and PB plasma,we detect the cytokine levels of MDS/AML patients and healthy donors by enzyme-linked immunosorbent assay(ELISA).Then,4 cases were collected before and after DAC chemotherapy for analysis of changes in cytokine levels after chemotherapy.To explore the origins and changes of increased cytokines,we isolated and cultured BM CD34~+cells and mesenchymal stem cells(MSCs)from MDS/AML patients and healthy donors in vitro,which were identified by flow cytometry.CD34~+cells and MSCs were treated with DAC in vitro.We detect the expression change of cytokines by real-time polymerase chain reaction(PCR).Results:Compared with those in healthy donors,there was no statistically difference in the levels of IL-1?and IL-10.However,the levels of IL-8 and IL-2R were significantly increased in MDS/AML patients.And the concentration of IL-6 was also elevated in MDS patients.But no statistical difference was found in AML patients.Strikingly,the IL-8 levels were remarkably elevated in MDS/AML patients with thrombocytopenia.Correlation analysis showed a significant inverse correlation between the IL-8level and the platelet counts in MDS/AML patients.Interestingly,the levels of IL-8 were markedly decreased after DAC treatment in vivo.In vitro detection demonstrated that the CD34~+cells and MSCs may be the extra sources of abnormally increased IL-8.DAC can dramatically lower the level of IL-8 in CD34~+cells and MSCs in vitro conditions.Conclusions and Discussion:The results of this study revealed that expression of the inflammation-associated cytokine IL-8 is increased both in MDS and AML patients,and the IL-8 is especially elevated in patients with thrombocytopenia.And the abnormal high amounts of IL-8 were derived from CD34~+cells and MSCs in the BM of MDS/AML patients.Importantly,for the first time,we demonstrated that decitabine chemotherapy improved PLT production by down-regulatingIL-8expressioninMDS/AMLpatientswith thrombocytopenia.These findings may reveal a novel mechanism in partly by which decitabine promotes PLT recovery in MDS/AML patients.