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 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.
Highlights
Chronic myeloid leukemia (CML) is a clonal myeloid neoplasm originating from malignant hematopoietic stem cells (HSCs) that express constitutively active, oncogenic Bcr-Abl1 kinase
We previously described a Bcr-Abl1-independent model of resistance to imatinib mesylate (IM) (K562-STI-R) in which CML K562 cells cultured in high concentration of IM displayed reduced Bcr-Abl1 protein and activity levels, and could withstand high concentrations of IM (Chorzalska et al, 2014)
Within the list of phosphopeptides showing statistically significant difference in abundancies between K562 and K562STI-R cells, we assessed the abundance of 275 MEKERK pathway-specific core interactor peptides (275 genes listed in the mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK) Pathway SuperPath http://pathcards.genecards.org/Pathway/273) and identified the Tpl2-derived phosphopeptide as the fourth most abundant in IM-resistant cells (Fig. 1, Table S2)
Summary
Chronic myeloid leukemia (CML) is a clonal myeloid neoplasm originating from malignant hematopoietic stem cells (HSCs) that express constitutively active, oncogenic Bcr-Abl kinase. With the discovery of a specific and potent tyrosine kinase inhibitor (TKI), imatinib, and its derivatives, dasatinib, nilotinib, bosutinib, and ponatinib (Druker et al, 1996; Golas et al, 2003; O’Hare et al, 2009; Shah et al, 2004; Weisberg et al, 2005), CML became a manageable chronic disease with a long-term survival exceeding 85%. Up to 25% of CML patients in the chronic phase experience disease progression during therapy with TKIs. While about 50% of these patients have mutations in the Bcr-Abl kinase domain (Castagnetti et al, 2017), it remains unclear why patients without these mutations lose their response to therapy
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