Overexpression of Tpl2 is linked to imatinib resistance and activation of MEK-ERK and NF-κB pathways in a model of chronic myeloid leukemia

Molecular Oncology
Anna ChorzalskaPatrycja M Dubielecka

Abstract

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 IMin 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 ...Continue Reading

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Citations

May 30, 2019·Journal of Experimental & Clinical Cancer Research : CR·Zhenhong LuoWenli Feng
May 11, 2019·International Journal of Molecular Sciences·Shu-Huey ChenChia-Hwa Lee
May 27, 2021·Brazilian Journal of Medical and Biological Research = Revista Brasileira De Pesquisas Médicas E Biológicas·Siya SunYuqing Ge

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Methods Mentioned

BETA
GTPase
ubiquitination
FACS
Transfection
acetylation

Software Mentioned

metacore [UNK]
facsdiva
SigmaPlot
R package QVALUE
mascot
[UNK] Real ‐ Time System

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