Open AccessOverexpression of Tpl2 is linked to imatinib resistance and activation of MEK ‐ ERK and NF ‐κB pathways in a model of chronic myeloid leukemia
Author(s) -
Chorzalska Anna,
Ahsan Nagib,
Rao R. Shyama Prasad,
Roder Karim,
Yu Xiaoqing,
Morgan John,
Tepper Alexander,
Hines Steven,
Zhang Peng,
Treaba Diana O.,
Zhao Ting C.,
Olszewski Adam J.,
Reagan John L.,
Liang Olin,
Gruppuso Philip A.,
Dubielecka Patrycja M.
Publication year - 2018
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12186
Subject(s) - myeloid leukemia , mapk/erk pathway , imatinib , chemistry , cancer research , medicine , kinase , biochemistry
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 ( COT 1) kinase or Map3k8. Overexpression of Tpl2 in IM ‐resistant cells was accompanied by elevated activities of Src family kinases ( SFK s) and NF ‐κB, MEK ‐ ERK signaling. CD 34+ cells isolated from the bone marrow of patients with CML and exposed to IM in vitro showed increased MAP 3K8 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 CD 34+ cells in methylcellulose assays by 80%. In addition, CML CD 34+ cells cultured with the combination of inhibitors showed reduced MAP 3K8 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 CD 34+ cells. Therefore, combination of SFK, MEK, and NF‐κB inhibitors may offer a new therapeutic approach to overcome TKI resistance in CML patients.