Chronic myeloid leukemia (CML) is a hematologic malignancy originating from BCR-ABL oncogene-transformed hematopoietic stem cells (HSCs) known as leukemia stem cells (LSCs). Therefore, targeting LSCs is of primary importance to eradicate CML. The present study demonstrates that picropodophyllin (PPP) effectively induces apoptosis and inhibits colony formation in CML stem/progenitor cells as well as quiescent CML progenitors resistant to imatinib therapy, while sparing normal hematopoietic cells in vitro. Administration of PPP in vivo markedly diminishes CML stem/progenitor cells in a transgenic mouse model of CML by inhibition of cell proliferation and enhancement of apoptosis in LSK cells, and significantly improves survival of CML mice. Furthermore, PPP treatment preferentially leads to transcriptional activation of p53 in CML but not normal CD34⁺ cells, upregulation of p53 protein in LSCs-enriched Sca-1⁺ cells from CML mice, and increased phosphorylation of p53 and upregulation of Bax protein in Ku812 cells. These results suggest that the inhibitory effects of PPP on CML stem/progenitor cells are associated with selective activation of p53 pathway and propose that PPP is a potent agent that selectively targets CML LSCs, and may be of value in the CML therapy.

慢性粒细胞白血病 (CML) 是一种血液系统恶性肿瘤，起源于 BCR-ABL 癌基因转化的造血干细胞 (HSC)，称为白血病干细胞 (LSC)。因此，靶向 LSCs 对于根除 CML 至关重要。本研究表明，鬼臼苦素 (PPP) 可有效诱导 CML 干细胞/祖细胞以及对伊马替尼治疗具有抗性的静止 CML 祖细胞的细胞凋亡和集落形成，同时在体外保护正常的造血细胞。体内PPP的给药通过抑制 LSK 细胞的细胞增殖和增强细胞凋亡，显着减少 CML 转基因小鼠模型中的 CML 干/祖细胞，并显着提高 CML 小鼠的存活率。此外，PPP 处理优先导致 CML 而非正常 CD34 ⁺细胞中 p53 的转录激活，来自 CML 小鼠富含 LSCs 的 Sca-1 ⁺细胞中 p53 蛋白的上调，以及在 Ku812 细胞中 p53 的磷酸化增加和 Bax 蛋白的上调. 这些结果表明 PPP 对 CML 干/祖细胞的抑制作用与 p53 通路的选择性激活有关，并提出 PPP 是一种选择性靶向 CML LSC 的有效药物，可能在 CML 治疗中具有价值。