Overexpression of Tpl2 is linked to imatinib resistance and activation of MEK-ERK and NF-κB pathways in a model of chronic myeloid leukemia.
Overexpression of Tpl2 is linked to imatinib resistance and activation of MEK-ERK and NF-κB pathways in a model of chronic myeloid leukemia.
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DOI：
10.1002/1878-0261.12186
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发表时间：
2018-05
影响因子：
6.6
通讯作者：
Dubielecka PM
中科院分区：
文献类型：
--
作者：
Chorzalska A;Ahsan N;Rao RSP;Roder K;Yu X;Morgan J;Tepper A;Hines S;Zhang P;Treaba DO;Zhao TC;Olszewski AJ;Reagan JL;Liang O;Gruppuso PA;Dubielecka PM
酪氨酸激酶抑制剂(TKI)的引入使慢性粒细胞白血病(CML)成为一种长期存活率超过85%的慢性疾病。然而，慢性粒细胞白血病干细胞对TKI的耐药性可能是TKI停用后分子缓解期复发率达到50%的原因之一。我们之前描述了一个对甲磺酸伊马替尼(IM)耐药的模型，在该模型中，在高浓度甲磺酸伊马替尼培养的K562细胞中，BCR-ABL1蛋白和活性水平降低，同时保持增殖潜力。利用对这些IM耐药细胞的定量磷酸蛋白质组学分析，我们现在已经发现肿瘤进展基因(Tpl2)显著上调，也被称为癌症大阪甲状腺(COT1)激酶或Map3k8。在IM耐药细胞中，Tpl2的过度表达伴随着sRc家族激酶(SFK)活性和NF-κB、MEK-ERK信号转导的增强。从CML患者骨髓分离的CD34+细胞体外暴露于IM后，MAP3K8转录水平升高。Dasatinib、U0126和PS-1145联合应用可消除65%的IM耐药细胞，并使CML CD34+细胞在甲基纤维素法中的集落形成能力降低80%。此外，与抑制剂联合培养的CML CD34+细胞显示MAP3K8转录水平降低。总体而言，我们的数据表明，Tpl2蛋白和转录水平的升高与IM耐药有关，联合抑制SFK、MEK和NF-κB信号可减弱IM耐药的慢性粒细胞白血病细胞和CML CD34+细胞的存活。因此，三者联合应用可能为克服慢性粒细胞白血病患者κ耐药提供一种新的治疗途径。
The introduction of tyrosine kinase inhibitors (TKI) has transformed chronic myeloid leukemia (CML) into a chronic disease with long‐term survival exceeding 85%. However, resistance of CML stem cells to TKI may contribute to the 50% relapse rate observed after TKI discontinuation in molecular remission. We previously described a model of resistance to imatinib mesylate (IM), in which K562 cells cultured in high concentrations of imatinib mesylate showed reduced Bcr‐Abl1 protein and activity levels while maintaining proliferative potential. Using quantitative phosphoproteomic analysis of these IM‐resistant cells, we have now identified significant upregulation of tumor progression locus (Tpl2), also known as cancer Osaka thyroid (COT1) kinase or Map3k8. Overexpression of Tpl2 in IM‐resistant cells was accompanied by elevated activities of Src family kinases (SFKs) and NF‐κB, MEK‐ERK signaling. CD34+ cells isolated from the bone marrow of patients with CML and exposed to IM in vitro showed increased MAP3K8 transcript levels. Dasatinib (SFK inhibitor), U0126 (MEK inhibitor), and PS‐1145 (IκB kinase (IKK) inhibitor) used in combination resulted in elimination of 65% of IM‐resistant cells and reduction in the colony‐forming capacity of CML CD34+ cells in methylcellulose assays by 80%. In addition, CML CD34+ cells cultured with the combination of inhibitors showed reduced MAP3K8 transcript levels. Overall, our data indicate that elevated Tpl2 protein and transcript levels are associated with resistance to IM and that combined inhibition of SFK, MEK, and NF‐κB signaling attenuates the survival of IM‐resistant CML cells and CML CD34+ cells. Therefore, combination of SFK, MEK, and NF‐κB inhibitors may offer a new therapeutic approach to overcome TKI resistance in CML patients.
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影响因子：
20.3
作者：
Guzman, ML;Neering, SJ;Jordan, CT
通讯作者：
Jordan, CT
影响因子：
20.3
作者：
Gallipoli, Paolo;Cook, Amy;Holyoake, Tessa L.
通讯作者：
Holyoake, Tessa L.
影响因子：
4.8
作者：
Favata, MF;Horiuchi, KY;Trzaskos, JM
通讯作者：
Trzaskos, JM
影响因子：
4.8
作者：
Boylan, JM;Gruppuso, PA
通讯作者：
Gruppuso, PA
DOI：
10.1073/pnas.0409856102
发表时间：
2005-02-15
影响因子：
11.1
作者：
Cho, JH;Tsichlis, PN
通讯作者：
Tsichlis, PN