Abstract
Nilotinib is a second-generation tyrosine kinase inhibitor, designed to specifically inhibit break-point cluster region (BCR)-Abelson (ABL) and developed to treat chronic myeloid leukemia (CML) in patients showing a resistance to imatinib. We previously demonstrated that nilotinib-induced apoptosis was reduced by stem cell factor (SCF) addition. Here, the SCF-activated survival pathway was investigated. BCR-ABL expression was accompanied by the activation of the SCF receptor: c-KIT. Nilotinib inhibited this activation that was restored by SCF binding. Parallel variations were observed for mammaliam target of rapamycin (mTOR) kinase and mTOR complex 1 substrate S6K. The inhibition of mTORC1 restored the response of BCR-ABL cell lines to nilotinib in the presence of SCF. PI3K inhibition restored nilotinib-induced apoptosis. On hematopoietic progenitors from CML patient's bone marrows, mTORC1 inhibition also restored nilotinib sensitivity in the presence of SCF, confirming its involvement in SCF-activated survival pathway. However, this pathway seems not to be involved in the nilotinib-induced resistance of the CML stem cell population. Conversely, PI3K inhibition sensitized both CML progenitors and stem cells to nilotinib, suggesting that, downstream PI3K, two different kinase pathways are activated in CML progenitor and stem cell populations.
Highlights
Chronic myeloid leukemia (CML) is a hematopoietic stem cell disease characterized by the presence of the chimeric breakpoint cluster region (BCR)-Abelson (ABL) gene, encoding a fusion protein with prominent tyrosine kinase activity.[1]
We previously demonstrated that SCF was able to inhibit nilotinib-induced apoptosis on BCRABL-expressing cells when nilotinib was used at concentrations targeting the BCR-ABL tyrosine kinase but was unable to inhibit the c-KIT tyrosine kinase.[9]
tyrosine kinase inhibitor (TKI)-induced imbalance between the BCL-2 family proteins was necessary for apoptosis,[16] it was not sufficient for the completion of this cell death, suggesting the inhibition of other antiapoptotic signals activated by BCR-ABL
Summary
Chronic myeloid leukemia (CML) is a hematopoietic stem cell disease characterized by the presence of the chimeric breakpoint cluster region (BCR)-Abelson (ABL) gene, encoding a fusion protein with prominent tyrosine kinase activity.[1] BCRABL has been identified as responsible for the leukemogenesis, leading to the development of a specific tyrosine kinase inhibitor (TKI): imatinib mesylate In vitro, it induces apoptosis in CML cells, without affecting normal cells.[2] In vivo, imatinib had totally revolutionized the treatment of CML patients, resulting in more than 80% of event-free survival after 8 years.[3,4] It currently constitutes the first-line treatment for CML patients. It is more specific as the nilotinib concentration required to block the BCR-ABL activity, that is, 20 nM, is not sufficient to inhibit c-KIT and platelet-derived growth factor receptor, to imatinib.[8]
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