Format

Send to

Choose Destination
Mol Oncol. 2018 May;12(5):630-647. doi: 10.1002/1878-0261.12186. Epub 2018 Apr 6.

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

Author information

1
Signal Transduction Lab, Division of Hematology/Oncology, Rhode Island Hospital, Warren Alpert Medical School, Brown University, Providence, RI, USA.
2
Division of Biology and Medicine, COBRE CCRD Proteomics Core Facility, Rhode Island Hospital, Brown University, Providence, RI, USA.
3
Division of Biostatistics and Bioinformatics, Yenepoya Research Center, Yenepoya University, Mangalore, India.
4
Cardiovascular Research Center, Rhode Island Hospital, Warren Alpert Medical School, Brown University, Providence, RI, USA.
5
Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA.
6
Flow Cytometry and Cell Sorting Core Facility, Roger Williams Medical Center, Providence, RI, USA.
7
Department of Pathology and Laboratory Medicine, Rhode Island Hospital, Warren Alpert Medical School, Brown University, Providence, RI, USA.
8
Cardiovascular Lab, Department of Surgery, Roger Williams Medical Center, Boston University School of Medicine, Providence, RI, USA.
9
Division of Hematology/Oncology, Rhode Island Hospital, Warren Alpert Medical School, Brown University, Providence, RI, USA.
10
Department of Pediatrics, Rhode Island Hospital, Brown University, Providence, RI, USA.

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 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.

KEYWORDS:

Bcr-Abl1; COT1; Map3k8; Tpl2; imatinib resistance; stem cells

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center