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FLT3-ITD induces expression of Pim kinases through STAT5 to confer resistance to the PI3K/Akt pathway inhibitors on leukemic cells by enhancing the mTORC1/Mcl-1 pathway
| Content Provider | Semantic Scholar |
|---|---|
| Author | Okada, Keigo Nogami, Ayako Ishida, Shinya Akiyama, Hiroki Chen, Cheng Umezawa, Yoshihiro Miura, Osamu |
| Copyright Year | 2017 |
| Abstract | FLT3-ITD is the most frequent tyrosine kinase mutation in acute myeloid leukemia (AML) associated with poor prognosis. We previously reported that activation of STAT5 confers resistance to PI3K/Akt inhibitors on the FLT3-ITD-positive AML cell line MV4-11 and 32D cells driven by FLT3-ITD (32D/ITD) but not by FLT3 mutated in the tyrosine kinase domain (32D/TKD). Here, we report the involvement of Pim kinases expressed through STAT5 activation in acquisition of this resistance. The specific pan-Pim kinase inhibitor AZD1208 as well as PIM447 in combination with the PI3K inhibitor GDC-0941 or the Akt inhibitor MK-2206 cooperatively downregulated the mTORC1/4EBP1 pathway, formation of the eIF4E/eIF4G complex, and Mcl-1 expression leading to activation of Bak and Bax to induce caspase-dependent apoptosis synergistically in these cells. These cooperative effects were enhanced or inhibited by knock down of mTOR or expression of its activated mutant, respectively. Overexpression of Mcl-1 conferred the resistance on 32D/ITD cells to combined inhibition of the PI3K/Akt pathway and Pim kinases, while the Mcl-1-specific BH3 mimetic A-1210477 conquered the resistance of MV4-11 cells to GDC-0941. Furthermore, overexpression of Pim-1 in 32D/TKD enhanced the mTORC1/Mcl-1 pathway and partially protected it from the PI3K/Akt inhibitors or the FLT3 inhibitor gilteritinib to confer the resistance to PI3K/Akt inhibitors. Finally, AZD1208 and GDC-0941 cooperatively inhibited the mTORC1/Mcl-1 pathway and reduced viable cell numbers of primary AML cells from some FLT3-ITD positive cases. Thus, Pim kinases may protect the mTORC1/4EBP1/Mcl-1 pathway to confer the resistance to the PI3K/Akt inhibitors on FLT3-ITD cells and represent promising therapeutic targets. |
| Starting Page | 8870 |
| Ending Page | 8886 |
| Page Count | 17 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | http://www.oncotarget.com/index.php?journal=oncotarget&op=download&page=article&path%5B%5D=22926&path%5B%5D=72352 |
| PubMed reference number | 29507660 |
| Alternate Webpage(s) | https://doi.org/10.18632/oncotarget.22926 |
| DOI | 10.18632/oncotarget.22926 |
| Journal | Oncotarget |
| Volume Number | 9 |
| Language | English |
| Access Restriction | Open |
| Subject Keyword | 1-Phosphatidylinositol 3-Kinase AZD1208 Apoptosis Cell Count FLT3 Inhibitor FRAP1 protein, human GDC 0941 Gilteritinib Leukemia, Myelocytic, Acute MCL1 gene MK 2206 Mutation Myeloid Leukemia Protein Tyrosine Kinase Proto-Oncogene Proteins c-akt STAT5A gene Tyrosine Kinase Domain |
| Content Type | Text |
| Resource Type | Article |
