β-Catenin is essential for survival of leukemic stem cells insensitive to kinase inhibition in mice with BCR-ABL-induced chronic myeloid leukemia
β-Catenin is essential for survival of leukemic stem cells insensitive to kinase inhibition in mice with BCR-ABL-induced chronic myeloid leukemia
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DOI：
10.1038/leu.2008.262
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发表时间：
2009-01-01
期刊：
影响因子：
11.4
通讯作者：
Li, S.
中科院分区：
文献类型：
--
作者：
Hu, Y.;Chen, Y.;Li, S.
由BCR-ABL癌基因诱导的费城染色体阳性（Ph+）慢性髓性白血病（CML）被认为是从白血病干细胞（LSC）发展而来的，我们之前已经在小鼠中表明，CML的LSC表达与正常造血干细胞（HSC）相同的细胞表面标志物。尽管伊马替尼对BCR-ABL激酶活性的抑制在治疗慢性期人Ph+ CML中非常有效，但难以实现疾病的分子缓解，这表明LSC仍留在患者体内。在这项研究中，我们发现伊马替尼治疗后，LSC不仅保留，而且在CML小鼠骨髓中积累增加。LSC对伊马替尼的这种不敏感性并不是因为伊马替尼缺乏BCR-ABL激酶抑制作用，并且来自LSC的增殖白血病细胞对伊马替尼的生长抑制仍然敏感。这些结果鉴定了不被伊马替尼抑制的LSC存活途径。此外，我们发现Wnt信号通路中的β-连环蛋白对于LSC的存活和自我更新至关重要，为靶向这些细胞提供了新的策略。
Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) induced by the BCR-ABL oncogene is believed to be developed from leukemic stem cells (LSCs), and we have previously shown in mice that LSCs for CML express the same cell surface markers that are also expressed on normal hematopoietic stem cells (HSCs). Although the inhibition of BCR-ABL kinase activity by imatinib is highly effective in treating human Ph+ CML in chronic phase, it is difficult to achieve molecular remission of the disease, suggesting that LSCs remain in patients. In this study, we find that following imatinib treatment, LSCs not only remained but also accumulated increasingly in bone marrow of CML mice. This insensitivity of LSCs to imatinib was not because of the lack of BCR-ABL kinase inhibition by imatinib, and proliferating leukemic cells derived from LSCs were still sensitive to growth inhibition by imatinib. These results identify an LSC survival pathway that is not inhibited by imatinib. Furthermore, we show that beta-catenin in the Wnt signaling pathway is essential for survival and self-renewal of LSCs, providing a new strategy for targeting these cells.