The Expression Signature And Clinical Significance Of HERG K+ Channels In Myelodysplastic Syndromes

Objective: HERG K+ channels, one of the evolutionary conserved family of voltage-activated K+ channels, are known to be constitutively expressed in multiple cell types such as neurons and cardiomyocytes, with an essential role in resting potential and action potential repolarization. However, growing experimental and preclinical data indicating that HERG potassium channels were preferential expressed in a vast number of human tumor cells of different histogenesis, whereas the corresponding non-cancerous cells have no significant HERG expression. Especially in non-solid carcinomas like acute myeloid leukemia(AML), HERG K+ channels are reported to contribute to tumor progression through facilitating cancer cell proliferation, migration, neoangiogenesis and chemotherapy resistance. With a highly risk of evolution into AML, MDS once were treated as the “pre-leukemia” condition. In recent years, a great deal of overlaps in the aberrantly expressed genomic spectrum have been present between MDS and AML. However, the expression profile and clinical significance of HERG in MDS are poorly understood. In this study, we identified the expression signatures of HERG K+ channels on bone marrow(BM) CD34+CD38- cells of MDS patients and analyzed correlation between HERG expression and clinical parameters of MDS, and tentative explored the role of HERG K+ channels in the biological processes of MDS cells.Methods: Bone marrow(BM) samples from 36 de novo MDS patients, 20 controls and 20 newly diagnosed AML patients were collected from Department of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China between March 2014 and February 2015. Flow cytometry was applied to detect the percentage of HERG K+ channels on CD34+CD38- cells. Then we investigated the relationship between percentage of HERG K+ channels on CD34+CD38- compartment and the WHO classification, routine blood parameters, and IPSS scores. In addition, with CCK-8 assay and flow cytometry, we analyzed the roles of E-4031 which was a blocking agent of HERG K+ channels in the proliferation, apoptosis and cell cycle of SKM-1 cells which is a kind of MDS cell line.Results: We found that HERG K+ channels on CD34+CD38- cells of MDS patients was associated with a higher percentage when compared to the control group(p(27) 0.01) and was lower than the AML patients(p(27) 0.05). By means of analyzing the clinical features of MDS patients, we observed that there was an obvious difference of HERG K+ channels percentage on CD34+CD38- cells between different MDS subgroups(p(27) 0.01), and percentage of HERG K+ channels on CD34+CD38- cells gradually increased from low to high grade MDS subtypes. Furthermore, we found that percentage of HERG K+ channels on CD34+CD38- cells was inversely associated with the neutrophil count(p(27) 0.05) and platelet count(p(27) 0.01). HERG K+ channels percentage on CD34+CD38-cells of the poor karyotype group was obvious higher than the good karyotype group(p(27) 0.05). And percentage of HERG K+ channels on CD34+CD38- cells showed an ascending tendency from low risk to high risk cohort(p(27) 0.01). In addition, E-4031 blockage in HERG K+ channels decreased the proliferation of MDS cells in a dose- and time-dependent manner(p(27) 0.01), but had rarely effects on cell apoptosis and cell cycle distribution.Conclusion: Our study showed that percentage of HERG K+ channels on CD34+CD38-cells of MDS patients was significant higher with respect to that of controls, and HERG K+ channels percentage on CD34+CD38- cells was positive correlated with the malignant degree of MDS and IPSS scores. These findings indicated that HERG K+ channels were likely to play important roles in the occurrence and development of MDS.Furthermore, the blockage in HERG K+ channels obviously suppressed the proliferation of SKM-1 cells, suggesting that Inhibition of HERG K+ channels might be a novel therapeutic measure for MDS.