Abstract
A small population of cancer stem cells named the “side population” (SP) has been demonstrated to be responsible for the persistence of many solid tumors. However, the role of the SP in leukemic pathogenesis remains controversial. The resistance of leukemic stem cells 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, ATP-binding cassette sub-family G member 2 (ABCG2), is well known as a specific marker of the SP and could be controlled by several pathways, including the PI3K/Akt pathway. Our data demonstrated that compared with 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 phosphatase and tensin homologue deleted on chromosome -10 (PTEN) and activated phosphorylated-Akt (p-Akt). PTEN and p-Akt downregulation could be abrogated by both the PI3K inhibitor LY294002 and the mTOR inhibitor rapamycin. Moreover, in CML patients in the accelerated phase/blastic phase (AP/BP), increased SP phenotype rather than ABCG2 expression was accompanied by the loss of PTEN protein and the up-regulation of p-Akt expression. These results suggested that the expression of ABCG2 and the SP may be regulated by PTEN through the PI3K/Akt pathway, which would be a potentially effective strategy for targeting CML stem cells.
Highlights
Chronic myeloid leukemia (CML) is a clonal bone marrow stem cell disorder that accounts for 7–20% of all leukemia cases and has an estimated incidence of 1–2 per 100,000 worldwide [1]
To determine whether ATP-binding cassette subfamily G member 2 (ABCG2) is related to CML resistance, the K562, K562/ABCG2 (ABCG2 overexpressing), K562/AO2 and K562/ IMR cell lines were exposed to 10 nM, 100 nM or 1 mM of mitoxantone
Compared with wild-type K562 cells, the subpopulation in the S phase was remarkably higher in K562/ABCG2, K562/AO2 and K562/ IMR cells when treated with 100 nM or 1 mM of mitoxantone (P,0.05)
Summary
Chronic myeloid leukemia (CML) is a clonal bone marrow stem cell disorder that accounts for 7–20% of all leukemia cases and has an estimated incidence of 1–2 per 100,000 worldwide [1]. The side population (SP), which can be identified and sorted by the efflux of Hoechst 33342, expresses stem cell properties, such as pluripotency and differentiation ability. ATP-binding cassette subfamily G member 2 (ABCG2), which is known as breast cancer resistance protein (BCRP), is defined as a specific marker of the SP in a variety types of stem cells based on its ability to efflux Hoechst 33342 [14,15,16]. The role of ABCG2 expression and the SP phenotype in the mechanism of resistance to TKI in CML stem cells remains unclear [17]. PTEN was described as regulating the SP but not the expression of ABCG2 in glioma tumor stem-like cells through the PI3K/Akt pathway [22]. We analyzed data from both CML cell lines and clinical samples from CML patients (Tab. 1)
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