The role of protein-tyrosine phosphatases for sensitivity and resistance of CML-cells to tyrosine-kinase inhibitors

Drube, Julia GND

Chronic myeloid leukemia (CML) is a disease of the hematopoietic system, caused by the expression of the constitutively active fusion protein-tyrosine kinase (PTK) BCR-ABL1. It can be successfully treated with specific tyrosine-kinase inhibitors (TKIs) targeting BCR-ABL1. Protein-tyrosine phosphatases (PTPs) may have an effect on TKI sensitivity and treatment response by modulating the transforming signaling activity of BCR-ABL1. The potential impact of specific PTPs on the therapeutic response to nilotinib in CML patients and on responses to nilotinib, imatinib, and dasatinib in CML cell lines was addressed in the current thesis. The individual patient treatment response was correlated with the PTP-status before the beginning of treatment. The mRNA expression levels of PTPRA, PTPRC, PTPRG, PTPRM, and PTPN13 were positively associated with a particularly good nilotinib treatment outcome. CRISPR/Cas9-mediated gene knockout (KO) or PTP over-expression were used to manipulate PTPRG and PTPRC expression levels in CML cell lines, and the impact on TKI response was measured by determination of the IC50 values for the TKIs in proliferation/viability assays. The KO of PTPRC or the over-expression of PTPRG caused a significant reduction of the IC50s for both nilotinib and imatinib. The colony-forming capacity was significantly reduced in PTPRC-KO and in PTPRG over-expressing cells. Assessment of BCR-ABL1 signaling revealed a reduction of SRC-family kinase activity and an elevation of the cell cycle inhibitor p27 in the engineered cell lines. Taken together it was shown that some PTPs contribute to treatment response to the TKI nilotinib and affect BCR-ABL mediated transformation. The knowledge of the underlying mechanisms may help to optimize therapeutic strategies and the mRNA expression levels of PTPs may be further explored as potential prognostic markers.

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Drube, Julia: The role of protein-tyrosine phosphatases for sensitivity and resistance of CML-cells to tyrosine-kinase inhibitors. Jena 2018.

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