TAL1 mediates imatinib-induced CML cell apoptosis via the PTEN/PI3K/AKT pathway
TAL1 mediates imatinib-induced CML cell apoptosis via the PTEN/PI3K/AKT pathway
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TAL1通过PTEN/PI3K/AKT途径介导伊马替尼诱导的CML细胞凋亡
DOI：
10.1016/j.bbrc.2019.08.164
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发表时间：
2019
影响因子：
3.1
通讯作者：
Zeng Chengwu
中科院分区：
文献类型：
--
作者：
Wu Yifan;Hu Yanyun;Yu Xibao;Zhang Yikai;Huang Xin;Chen Shaohua;Li Yangqiu;Zeng Chengwu
慢性粒细胞白血病（CML）与染色体易位t（9; 22）相关，导致BCR-ABL癌基因的形成。CML用靶向BCR-ABL的酪氨酸激酶抑制剂（TKI）治疗，以根除BCR-ABL +细胞。然而，TKI伊马替尼（IM）未能消除CML中的静止白血病干细胞（LSC）。在这项研究中，我们证明转录因子TAL 1在CML LSC中被BCR-ABL下调，IM触发TAL 1 mRNA表达。此外，TAL 1的缺失消除了IM诱导的CML细胞凋亡。RNA-seq分析表明TAL 1表达可能影响PI 3 K/AKT通路。此外，TAL 1的消耗抑制了PTEN的表达，其是PI 3 K/AKT途径的负调节剂。我们的研究结果揭示了TAL 1在CML病因学中的意想不到的参与，并证明TAL 1可以调节PTEN表达，并导致CML细胞对TKI的反应中的PI 3 K/AKT通路的抑制。这些结果暗示调节PTEN表达是CML中TAL 1转录调控网络的一种新机制。
Chronic myeloid leukemia (CML) is associated with chromosomal translocation t(9; 22), which results in formation of the BCR-ABL oncogene. CML is treated with tyrosine kinase inhibitors (TKIs), which target BCR-ABL, to eradicate BCR-ABL + cells. However, the TKI imatinib (IM) fails to eliminate quiescent leukemia stem cells (LSCs) in CML. In this study, we demonstrate that transcription factor TAL1 is down-regulated in CML LSCs by BCR-ABL, and IM triggers TAL1 mRNA expression. In addition, loss of TAL1 abrogates IM-induced CML cell apoptosis. RNA-seq analysis suggests that TAL1 expression may affect PI3K/AKT pathway. Moreover, depletion of TAL1 inhibits the expression of PTEN, which is a negative regulator of the PI3K/AKT pathway. Our results reveal an unexpected involvement of TAL1 in CML etiology and demonstrate that TAL1 may regulate PTEN expression and lead to inhibition of the PI3K/AKT pathway in the response of CML cells to TKI. These results implicate regulation of PTEN expression as a novel mechanism for the transcriptional regulatory networks of TAL1 in CML.