The antiproliferative activity of kinase inhibitors in chronic myeloid leukemia cells is mediated by FOXO transcription factors.
The antiproliferative activity of kinase inhibitors in chronic myeloid leukemia cells is mediated by FOXO transcription factors.
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DOI：
10.1002/stem.1748
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发表时间：
2014-09
期刊：
影响因子：
5.2
通讯作者：
Holyoake, Tessa L.
中科院分区：
文献类型：
--
作者：
Pellicano, Francesca;Scott, Mary T.;Helgason, G. Vignir;Hopcroft, Lisa E. M.;Allan, Elaine K.;Aspinall-O'Dea, Mark;Copland, Mhairi;Pierce, Andrew;Huntly, Brian J. P.;Whetton, Anthony D.;Holyoake, Tessa L.
关键词：
慢性粒细胞白血病(CML)是由酪氨酸激酶BCR-ABL启动和维持的，它激活了包括PI3K/AKT信号在内的一系列信号转导通路，从而使FOXO转录因子失活。ABL特异性酪氨酸激酶抑制剂(TKIs)诱导CML祖细胞最小程度的凋亡，但通过尚不清楚的机制发挥强大的抗增殖作用。在这里，我们证明了在CD34+CML细胞中，FOXO1和3a被BCR-ABL活性灭活并重新定位到细胞质中。TKI导致FOXO的磷酸化水平降低，导致FOXO从胞浆(非活性)到胞核(活性)的重新定位，在那里它们调节关键的FOXO靶基因如Cyclin D1、ATM、CDKN1C和BCL6的表达，并诱导G1期停滞。在CML转基因小鼠模型中，达沙替尼体内治疗6天后，FOXO1和3a也被激活，其靶基因Cyclin D1的表达降低。FOXO3a在CML细胞中的过度表达与TKI联合抑制增殖，PI3K/AKT/mTOR信号通路的抑制剂也有类似的结果。稳定表达活性的FOXO3a突变体可诱导与单独TKI相似的静止期，而shRNA介导的FOXO3a基因敲除可使CML细胞进入细胞周期，并增强TKI诱导的细胞凋亡。这些结果表明，TKI诱导CML细胞G1期停滞是通过抑制PI3K/AKT通路和重新激活FOXO来实现的。这加强了对TKI活性和诱导的祖细胞静止的理解，表明CML的新治疗策略应该集中在操纵这一信号网络上。干细胞2014；32：2324-2337
Chronic myeloid leukemia (CML) is initiated and maintained by the tyrosine kinase BCR-ABL which activates a number of signal transduction pathways, including PI3K/AKT signaling and consequently inactivates FOXO transcription factors. ABL-specific tyrosine kinase inhibitors (TKIs) induce minimal apoptosis in CML progenitor cells, yet exert potent antiproliferative effects, through as yet poorly understood mechanisms. Here, we demonstrate that in CD34+ CML cells, FOXO1 and 3a are inactivated and relocalized to the cytoplasm by BCR-ABL activity. TKIs caused a decrease in phosphorylation of FOXOs, leading to their relocalization from cytoplasm (inactive) to nucleus (active), where they modulated the expression of key FOXO target genes, such as Cyclin D1, ATM, CDKN1C, and BCL6 and induced G1 arrest. Activation of FOXO1 and 3a and a decreased expression of their target gene Cyclin D1 were also observed after 6 days of in vivo treatment with dasatinib in a CML transgenic mouse model. The over-expression of FOXO3a in CML cells combined with TKIs to reduce proliferation, with similar results seen for inhibitors of PI3K/AKT/mTOR signaling. While stable expression of an active FOXO3a mutant induced a similar level of quiescence to TKIs alone, shRNA-mediated knockdown of FOXO3a drove CML cells into cell cycle and potentiated TKI-induced apoptosis. These data demonstrate that TKI-induced G1 arrest in CML cells is mediated through inhibition of the PI3K/AKT pathway and reactivation of FOXOs. This enhanced understanding of TKI activity and induced progenitor cell quiescence suggests that new therapeutic strategies for CML should focus on manipulation of this signaling network. Stem Cells 2014;32:2324–2337
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