The introduction of second-generation tyrosine kinase inhibitors (TKIs) targeting the protein-tyrosine kinase (PTK) BCR-ABL1 has improved treatment response in chronic myeloid leukemia (CML). However, in some patients response still remains suboptimal. Protein-tyrosine phosphatases (PTPs) are natural counter-actors of PTK activity and can affect TKI sensitivity, but the impact of PTPs on treatment response to second-generation TKIs is unknown. We assessed the mRNA expression level of 38 PTPs in 66 newly diagnosed CML patients and analyzed the potential relation with treatment outcome after 9 months of nilotinib medication. A significantly positive association with response was observed for higher PTPN13, PTPRA, PTPRC (also known as CD45), PTPRG, and PTPRM expression. Selected PTPs were then subjected to a functional analysis in CML cell line models using PTP gene knockout by CRISPR/ Cas9 technology or PTP overexpression. These analyses revealed PTPRG positively and PTPRC negatively modulating nilotinib response. Consistently, PTPRG negatively and PTPRC positively affected BCR-ABL1 dependent transformation. We identified BCR-ABL1 signaling events, which were affected by modulating PTP levels or nilotinib treatment in the same direction. In conclusion, the PTP status of CML cells is important for the response to second generation TKIs and may help in optimizing therapeutic strategies

PTPRG and PTPRC modulate nilotinib response in chronic myeloid leukemia cells

Claudio Sorio
Resources
;
2018

Abstract

The introduction of second-generation tyrosine kinase inhibitors (TKIs) targeting the protein-tyrosine kinase (PTK) BCR-ABL1 has improved treatment response in chronic myeloid leukemia (CML). However, in some patients response still remains suboptimal. Protein-tyrosine phosphatases (PTPs) are natural counter-actors of PTK activity and can affect TKI sensitivity, but the impact of PTPs on treatment response to second-generation TKIs is unknown. We assessed the mRNA expression level of 38 PTPs in 66 newly diagnosed CML patients and analyzed the potential relation with treatment outcome after 9 months of nilotinib medication. A significantly positive association with response was observed for higher PTPN13, PTPRA, PTPRC (also known as CD45), PTPRG, and PTPRM expression. Selected PTPs were then subjected to a functional analysis in CML cell line models using PTP gene knockout by CRISPR/ Cas9 technology or PTP overexpression. These analyses revealed PTPRG positively and PTPRC negatively modulating nilotinib response. Consistently, PTPRG negatively and PTPRC positively affected BCR-ABL1 dependent transformation. We identified BCR-ABL1 signaling events, which were affected by modulating PTP levels or nilotinib treatment in the same direction. In conclusion, the PTP status of CML cells is important for the response to second generation TKIs and may help in optimizing therapeutic strategies
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11562/973827
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