Enhanced activation of STAT pathways and overexpression of survivin confer resistance to FLT3 inhibitors and could be therapeutic targets in AML
In: Blood, Jg. 113 (2009), Heft 17, S. 4052-4062
Online
academicJournal
- print, 54 ref
Zugriff:
To further investigate potential mechanisms of resistance to FLT3 inhibitors, we developed a resistant cell line by long-term culture of MV4-11 cells with ABT-869, designated as MV4-11-R. Gene profiling reveals up-regulation of FLT3LG(FLT3 ligand) and BIRC5 (survivin), but down-regulation of SOCS1, SOCS2, and SOCS3 in MV4-11-R cells. Hypermethylation of these SOCS genes leads to their transcriptional silencing. Survivin is directly regulated by STAT3. Stimulation of the parental MV4-11 cells with FLT3 ligand increases the expression of survivin and phosphorylated protein STAT1, STAT3, STATS. Targeting survivin by short-hairpin RNA (shRNA) in MV4-11-R cells induces apoptosis and augments ABT-869-mediated cytotoxicity. Overexpression of survivin protects MV4-11 from apoptosis. Sub-toxic dose of indirubin derivative (IDR) E804 resensitizes MV4-11-R to ABT-869 treatment by inhibiting STAT signaling activity and abolishing survivin expression. Combining IDR E804 with ABT-869 shows potent in vivo efficacy in the MV4-11-R xenograft model. Taken together, these results demonstrate that enhanced activation of STAT pathways and overexpression of survivin are important mechanisms of resistance to ABT-869, suggesting that the STAT pathways and survivin could be potential targets for reducing resistance developed in patients receiving FLT3 inhibitors.
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Enhanced activation of STAT pathways and overexpression of survivin confer resistance to FLT3 inhibitors and could be therapeutic targets in AML
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Autor/in / Beteiligte Person: | JIANBIAO, ZHOU ; BI, Chonglei ; GLASER, Keith B ; ALBERT, Daniel H ; DAVIDSEN, Steven K ; CHEN, Chien-Shing ; JANAKAKUMARA, Jasinghe V ; LIU, Shaw-Cheng ; CHNG, Wee-Joo ; TAY, Kian-Ghee ; POON, Lai-Fong ; ZHIGANG, XIE ; PALANIYANDI, Senthilnathan ; YU, Hanry |
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Zeitschrift: | Blood, Jg. 113 (2009), Heft 17, S. 4052-4062 |
Veröffentlichung: | Washington, DC: Americain Society of Hematology, 2009 |
Medientyp: | academicJournal |
Umfang: | print, 54 ref |
ISSN: | 0006-4971 (print) |
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