Neither cell line SUP B15 nor most other TKI resistant cell lines showed particularly high BCR ABL1 expression levels based on quantita tive RT PCR analysis. The only exception was cell line KCL 22 with about 2 fold higher BCR ABL1 expression levels, each at the mRNA plus the protein level. Even though supporting the notion that a causative correlation may possibly exist in between the higher expression on the mutated kinase and imatinib resistance for cell line KCL 22, these outcomes also showed that in four five cell lines TKI resistance was not the conse quence of BCR ABL1 overexpression. Therefore, neither BCR ABL1 mutations nor overexpres sion in the kinase were the basic result in for imatinib resistance in these cell lines. Additional analyses showed that also dysregulation of drug transporters was improb able, in contrast to imatinib, nilotinib is neither imported via hOCT 1, nor exported by way of ABCB1.
All five imati nib resistant cell lines were nilotinib resistant. Thus, it appeared unlikely that imatinib resistance was brought on by deregulated transport proteins. Lastly, the discovering that each imatinib and nilotinib induced dephosphorylation of signal transducer and activator of transcription five in the TKI resistant NSC14613 cell line SUP B15 as shown in Figure 2 additional excludes resis tance being as a consequence of low intracellular drug levels. Both drugs were transported in to the cells which responded by dephosphorylating STAT5 though retaining viability. SRC kinases SRC kinases had been described to play a vital role in BCR ABL1 good ALL. Interest ingly, 4 five imatinib resistant Ph cell lines were from individuals with pre B ALL, T ALL, or CML in B cell blast crisis.
Amongst lymphoid Ph cell lines 5 7 were imatinib resistant, like TOM 1, a pre B cell line classed semiresistant displaying typical IC50 values inside the thymidine uptake assay when remaining reasonably unresponsive to larger concentrations. There fore, we applied dasatinib to elucidate regardless of whether activity these details of SRC kinases was crucial for the growth of imatinib resistant cells. Dasatinib is a dual BCR ABL1 and SRC kinase inhibitor, as evidenced by its ability to inhibit phosphorylation of SRC and STAT5 in TKI responsive JURL MK2 cells. Nevertheless, two of 3 imatinib resistant cell lines tested have been resistant to dasatinib inside the proliferation assay. In addition, TKI resistant SUP B15 cells did not express an active, phosphorylated SRC kinase and dasatinib did not affect RSP6 phosphorylation within this cell line.
These final results will not be consistent with all the notion that SRC kinases would be the reason for imati nib resistance in these cell lines. Imatinib induces dephosphorylation of ERK1 2 and of STAT5 in TKI resistant cell lines BCR ABL1 optimistic cells are characterized by stimulation with the Janus kinase two STAT5, extracellular signal regulated kinase 1 2 and phosphoinositide three kinase v Akt murine thymoma viral oncogene homolog 1 mammalian target of rapamycin pathways.
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