PTEN Regulated BCRP/ABCG2 and Side Population Through PI3K/Akt Pathway In Chronic Myeloid Leukemia

A small population of cancer stem cells named as “side population (SP)” has been demonstrated to be responsible for many solid tumor maintenance. However, the role of SP in leukemic pathogenesis is still controversial. The resistance of leukemic stem cells in response to targeted therapies such as tyrosine kinase inhibitors (TKIs) results in therapeutic failure or refractory/relapsed disease in chronic myeloid leukemia (CML). The drug pump, ABCG2, is well-known as a specific marker of SP and could be controlled by several pathways including PI3K/Akt. Our data demonstrated that compared to wild type K562 cells, the higher percentage of ABCG2+ cells corresponded to the higher SP fraction in K562/ABCG2 (ABCG2 overexpressing) and K562/IMR (resistance to imatinib) cells, which exhibited enhanced drug resistance along with downregulated PTEN and activated p-Akt. It could be abrogated by both PI3K inhibitor LY294002 and mTOR inhibitor rapamycin. Moreover, in CML patients at accelerated phase/blastic phase (AP/BP), increased SP phenotype rather than ABCG2 expression accompanied with loss of PTEN protein and up-regulation of p-Akt expression was observed. These results suggested that expression of ABCG2 and fraction of SP may be regulated by PTEN through PI3K/Akt pathway, which will be the potentially effective strategy for targeting CML stem cells.