The Role Of Autophagy In The Process Of Myelodysplastic Syndrome

Objective:Myelodysplastic syndromes(MDS) are a group of clonal hematopoietic stem / progenitor cell disorders, which is characterized by dysplastic changes in bone marrow, ineffective hematopoiesis resulting in cytopenias, may accompanied by an increase in blasts and an increased risk of developing acute myeloid leukemia(AML) in a third of patients,currently its pathogenesis is not yet entirely clear. Autophagy as the type II programmed cell death, has been proved to play an important role in the pathogenesis and prognosis of hematologic malignancies. But it rarely been reported in MDS. This study was designed to detect the activity of autophagy in patients with myelodysplastic syndrome, and tried to investigate the roles of autophagy in MDS.Method:(1)Using Real-time quantitative Polymerase Chain Reaction(q RT-PCR) technique to investigate the expression level of LC3 B m RNA in bone marrow mononuclear cells(BMNCs)from 64 MDS,20 non-malignant anemia, and 28 de novo acute myeloid leukemia(AML).And then analyze the relationship between the expression of LC3 B and the World Health Organization classification-based prognostic system(WPSS) of the MDS patients.(2) At the same time we use Western-blot to detect the expression of LC3 B protein of the patients.(3) Investigate the activity of autophagy in bone marrow CD34+ cells from 20 MDS,20 non-malignant anemia, and 5 de novo AML by flow cytometry(FCM). Then analyze the relationship between the activity of autophagy and the World Health Organization classification-based prognostic system(WPSS) of the MDS patients.Result:(1) The expression of LC3 B was significantly higher in non-malignant anemia than high-risk MDS(P=0.003) and AML(P=0);in low-risk MDS(WPSS score<3) than that in high-risk MDS(WPSS score≥3)(P=0.004) and AML(P=0) at m RNA levels; non-malignant anemia compared with low-risk MDS group had no significant difference(P=0.128). The WPSS score was negatively correlated with the expression level of LC3 B gene in MDS patients(P=0.01;r =-0.324).(2) The expression of LC3 B protein level was almost consistent with the m RNA level.(3)The activity of autophagy in patients bone marrow CD34+cells were almost same as that in the m RNA level and protein level of LC3 B. The activity of autophagy was significantly higher in non-malignant anemia than high-risk MDS(P=0) and AML(P=0);in low-risk MDS(WPSS score<3) than that in high-risk MDS(WPSS score≥3)(P=0.04) and AML(P=0.01); non-malignant anemia compared with low-risk MDS group had no significant difference(P=0.903); and the high-risk MDS compared with the AML group,the difference was not statistically significant(P=0.564).The activity of autophagy in bone marrow CD34+ cells was negatively correlated with the WPSS score(r=-0.887).Conclusion:Our findings strongly suggest that an weak activity of autophagy occurred in high-risk MDS and AML, the activity of autophagy may be involved in the pathogenesis and prognosis of MDS.