The DOI matches its Crossref record; 7 of the 7 references it cites were found in a registry or an index.
Enhanced activation of STAT pathways and overexpression of survivin confer resistance to FLT3 inhibitors and could be therapeutic targets in AML
Abstract
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, STAT5. 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. Subtoxic 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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Cites
Clinical Resistance to STI-571 Cancer Therapy Caused by BCR-ABL Gene Mutation or Amplification
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Validating Stat3 in cancer therapy
Darnell, J. E. (2005) · Nature Medicine · doi:10.1038/nm0605-595 · Cited by 307
Differential hypermethylation of SOCS genes in ovarian and breast carcinomas
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‘Acute myeloid leukemia: a comprehensive review and 2016 update’
De Kouchkovsky, I., & Abdul-Hay, M. (2016) · Blood Cancer Journal · doi:10.1038/bcj.2016.50 · Cited by 1,317
Ravandi, F., Alattar, M. L., Grunwald, M. R., Rudek, M. A., Rajkhowa, T., Richie, M. A., Pierce, S., Daver, N., Garcia-Manero, G., Faderl, S., et al. (2013) · Blood · doi:10.1182/blood-2013-01-480228 · Cited by 381
Targeting Stat3 Abrogates EGFR Inhibitor Resistance in Cancer
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Aberrant splicing and drug resistance in AML
de Necochea-Campion, R., Shouse, G. P., Zhou, Q., Mirshahidi, S., & Chen, C.-S. (2016) · Journal of Hematology & Oncology · doi:10.1186/s13045-016-0315-9 · Cited by 66
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Metadata
- Authors
- Zhou, J., Bi, C., Janakakumara, J. V., Liu, S.-C., Chng, W.-J., Tay, K.-G., Poon, L.-F., Xie, Z., Palaniyandi, S., Yu, H., Glaser, K. B., Albert, D. H., Davidsen, S. K., & Chen, C.-S.
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2009-04-23
- Volume
- 113
- Issue
- 17
- Pages
- 4052-4062
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2069931679
- Cited by
- 162
- References
- 7
- FWCI
- 9.71
- Type
- journal article
- Language
- en
- Open access
- closed
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- The paper
- Zhou, J., Bi, C., Janakakumara, J. V., Liu, S.-C., Chng, W.-J., Tay, K.-G., Poon, L.-F., Xie, Z., Palaniyandi, S., Yu, H., Glaser, K. B., Albert, D. H., Davidsen, S. K., & Chen, C.-S. (2009). Enhanced activation of STAT pathways and overexpression of survivin confer resistance to FLT3 inhibitors and could be therapeutic targets in AML. Blood. https://doi.org/10.1182/blood-2008-05-156422
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