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Therapeutic targeting of the MEK/MAPK signal transduction module in acute myeloid leukemia
Open accessAbstract
The mitogen-activated protein kinase (MAPK) pathway regulates growth and survival of many cell types, and its constitutive activation has been implicated in the pathogenesis of a variety of malignancies. In this study we demonstrate that small-molecule MEK inhibitors (PD98059 and PD184352) profoundly impair cell growth and survival of acute myeloid leukemia (AML) cell lines and primary samples with constitutive MAPK activation. These agents abrogate the clonogenicity of leukemic cells but have minimal effects on normal hematopoietic progenitors. MEK blockade also results in sensitization to spontaneous and drug-induced apoptosis. At a molecular level, these effects correlate with modulation of the expression of cyclin-dependent kinase inhibitors (p27(Kip1) and p21(Waf1/CIP1)) and antiapoptotic proteins of the inhibitor of apoptosis proteins (IAP) and Bcl-2 families. Interruption of constitutive MEK/MAPK signaling therefore represents a promising therapeutic strategy in AML.
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Cited by
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Schenk, T., Stengel, S., & Zelent, A. (2014) · British Journal of Cancer · doi:10.1038/bjc.2014.412 · Cited by 160
Tabe, Y., Konopleva, M., Munsell, M. F., Marini, F. C., Zompetta, C., McQueen, T., Tsao, T., Zhao, S., Pierce, S., Igari, J., et al. (2004) · Blood · doi:10.1182/blood-2003-03-0802 · Cited by 93
Self-citationTabe, Y., Sebasigari, D., Jin, L., Rudelius, M., Davies-Hill, T., Miyake, K., Miida, T., Pittaluga, S., & Raffeld, M. (2009) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-08-0399 · Cited by 83
Zhang, W., Konopleva, M., Burks, J. K., Dywer, K. C., Schober, W. D., Yang, J.-Y., McQueen, T. J., Hung, M.-C., & Andreeff, M. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-0878 · Cited by 70
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Metadata
- Authors
- Milella, M., Kornblau, S. M., Estrov, Z., Carter, B. Z., Lapillonne, H., Harris, D., Konopleva, M., Zhao, S., Estey, E., & Andreeff, M.
- Venue
- Journal of Clinical Investigation
- Published
- 2001-09-15
- Volume
- 108
- Issue
- 6
- Pages
- 851-859
- ISSN
- 0021-9738 (ISSN-L)
- OpenAlex
- W2122051507
- Cited by
- 312
- References
- 0
- FWCI
- 8.58
- Type
- journal article
- Language
- en
- Open access
- green
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- Milella, M., Kornblau, S. M., Estrov, Z., Carter, B. Z., Lapillonne, H., Harris, D., Konopleva, M., Zhao, S., Estey, E., & Andreeff, M. (2001). Therapeutic targeting of the MEK/MAPK signal transduction module in acute myeloid leukemia. Journal of Clinical Investigation. https://doi.org/10.1172/jci12807
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