PI3K/mTOR pathway inhibitors sensitize chronic myeloid leukemia stem cells to nilotinib and restore the response of progenitors to nilotinib in the presence of stem cell factor.
PI3K/mTOR pathway inhibitors sensitize chronic myeloid leukemia stem cells to nilotinib and restore the response of progenitors to nilotinib in the presence of stem cell factor.
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DOI：
10.1038/cddis.2013.309
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发表时间：
2013-10-03
影响因子：
9
通讯作者：
中科院分区：
文献类型：
--
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尼洛替尼是第二代酪氨酸激酶抑制剂，专为抑制断点簇区(BCR)-Abelson(ABL)而设计，用于治疗对伊马替尼耐药的慢性粒细胞白血病(CML)患者。我们先前已经证明，加入干细胞因子(SCF)可以减少尼洛替尼诱导的细胞凋亡。在此，我们对干细胞因子激活的生存途径进行了研究。Bcr-abl的表达伴随着SCF受体C-KIT的激活。尼洛替尼抑制通过SCF结合而恢复的这种激活。雷帕霉素(MTOR)激酶的哺乳动物靶标和mTOR复合体1底物S6K存在平行变异。抑制mTORC1可恢复BCR-ABL细胞对干细胞因子尼洛替尼的反应。抑制PI3K可恢复尼洛替尼诱导的细胞凋亡。在CML患者的骨髓造血祖细胞上，抑制mTORC1也恢复了在SCF存在下对尼洛替尼的敏感性，证实了其参与了SCF激活的生存通路。然而，这一途径似乎与尼洛替尼诱导的慢性粒细胞白血病干细胞群耐药无关。相反，抑制PI3K使CML祖细胞和干细胞对尼洛替尼敏感，这表明在PI3K下游，CML祖细胞和干细胞群体中有两种不同的激酶途径被激活。
Nilotinib is a second-generation tyrosine kinase inhibitor, designed to specifically inhibit break-point cluster region (BCR)-Abelson (ABL) and developed to treat chronic myeloid leukemia (CML) in patients showing a resistance to imatinib. We previously demonstrated that nilotinib-induced apoptosis was reduced by stem cell factor (SCF) addition. Here, the SCF-activated survival pathway was investigated. BCR-ABL expression was accompanied by the activation of the SCF receptor: c-KIT. Nilotinib inhibited this activation that was restored by SCF binding. Parallel variations were observed for mammaliam target of rapamycin (mTOR) kinase and mTOR complex 1 substrate S6K. The inhibition of mTORC1 restored the response of BCR-ABL cell lines to nilotinib in the presence of SCF. PI3K inhibition restored nilotinib-induced apoptosis. On hematopoietic progenitors from CML patient's bone marrows, mTORC1 inhibition also restored nilotinib sensitivity in the presence of SCF, confirming its involvement in SCF-activated survival pathway. However, this pathway seems not to be involved in the nilotinib-induced resistance of the CML stem cell population. Conversely, PI3K inhibition sensitized both CML progenitors and stem cells to nilotinib, suggesting that, downstream PI3K, two different kinase pathways are activated in CML progenitor and stem cell populations.
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影响因子：
158.5
作者：
Apperley, JF;Gardembas, M;Goldman, JM
通讯作者：
Goldman, JM
DOI：
10.1073/pnas.0400063101
发表时间：
2004-03-02
影响因子：
11.1
作者：
Mohi, MG;Boulton, C;Neel, BG
通讯作者：
Neel, BG
影响因子：
11.5
作者：
Deininger, Michael W.
通讯作者：
Deininger, Michael W.
影响因子：
20.3
作者：
Kantarjian, Hagop M.;Giles, Francis;le Coutre, Philipp
通讯作者：
le Coutre, Philipp
影响因子：
20.3
作者：
Akin, C;Fumo, G;Metcalfe, DD
通讯作者：
Metcalfe, DD