Abstract
Acute myeloid leukemia (AML) is a malignant tumor of the hematopoietic system, and leukemia stem cells are responsible for AML chemoresistance and relapse. KG-1a cell is considered a leukemia stem cell-enriched cell line, which is resistant to chemotherapy. Arsenic trioxide (ATO) is effective against acute promyelocytic leukemia as a first-line treatment agent, even as remission induction of relapsed cases. ATO has a cytotoxic effect on KG-1a cells, but the mechanism remains unclear. Our results demonstrated that ATO can inhibit cell proliferation, induce apoptosis, and arrest KG-1a cells in the G2/M phase. Using transcriptome analysis, we investigated the candidate target genes regulated by ATO in KG-1a cells. The expression profile analysis showed that the ATO had significantly changed gene expression related to proliferation, apoptosis, and cell cycle. Moreover, MYC, PCNA, and MCM7 were identified as crucial hub genes through protein–protein interaction network analysis; meanwhile, the expressions of them in both RNA and protein levels are down-regulated as confirmed by quantitative polymerase chain reaction and Western blot. Thus, our study suggests that ATO not only inhibits the expression of MYC, PCNA, and MCM7 but also leads to cell cycle arrest and apoptosis in KG-1a cells. Overall, this study provided reliable clues for improving the ATO efficacy in AML.
Highlights
Acute myeloid leukemia (AML) is a type of malignant clonal disease originating from hematopoietic stem cells, which are highly heterogeneous (Dohner et al, 2015)
We focused only on the terms related to apoptosis and cell cycle and picked up the differentially expressed genes (DEGs) participating in these terms; after that, we used the STRING database to get the PPI network
We found that Arsenic trioxide (ATO) has a dosage-dependent inhibitory effect on the proliferation of KG-1a cells (Figure 1A)
Summary
Acute myeloid leukemia (AML) is a type of malignant clonal disease originating from hematopoietic stem cells, which are highly heterogeneous (Dohner et al, 2015). The 5-year survival rate of AML Non-Acute promyelocytic leukemia is still less than 30%, and most patients will eventually relapse (Pullarkat and Aldoss, 2015). KG-1a cell line, derived from a male AML patient, has the characteristics of leukemia stem cells, such as self-renewal, differentiation, and the phenotype of CD34+CD38−. Arsenic trioxide (ATO) combined with all-trans retinoic acid has been used clinically for the treatment of PML-RARα-positive acute promyelocytic leukemia, achieving the current remarkable cure rates (Jeanne et al, 2010). A previous study about AML revealed that TRPM4 being the only gene encoding a surface protein up-regulated in four AML cell lines after induction by azacitidine treatment (Leung et al, 2019). There is no report about the gene expression profile of KG-1a cells induced by ATO treatment using transcriptome sequencing. This study showed that ATO induced significant antiproliferative effects and obvious apoptosis in KG1a cells through inhibiting the expression of MYC, PCNA, MCM7, and BCL2L1
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