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PKC412 inhibits the zinc finger 198-fibroblast growth factor receptor 1 fusion tyrosine kinase and is active in treatment of stem cell myeloproliferative disorder
Open accessAbstract
Human stem cell leukemia-lymphoma syndrome usually presents itself as a myeloproliferative disorder (MPD) that evolves to acute myeloid leukemia and/or lymphoma. The syndrome associated with t(8;13)(p11;q12) results in expression of the ZNF198-fibroblast growth factor receptor (FGFR) 1 fusion tyrosine kinase. Current empirically derived cytotoxic chemotherapy is inadequate for treatment of this disease. We hypothesized that small-molecule inhibitors of the ZNF198-FGFR1 fusion would have therapeutic efficacy. We characterized the transforming activity of ZNF198-FGFR1 in hematopoietic cells in vitro and in vivo . Expression of ZNF198-FGFR1 in primary murine hematopoietic cells caused a myeloproliferative syndrome in mice that recapitulated the human MPD phenotype. Transformation in these assays, and activation of the downstream effector molecules PLC-γ, STAT5, and phosphatidylinositol 3-kinase/AKT, required the proline-rich domains, but not the ZNF domains, of ZNF198. A small-molecule tyrosine kinase inhibitor, PKC412 ( N -benzoyl-staurosporine) effectively inhibited ZNF198-FGFR1 tyrosine kinase activity and activation of downstream effector pathways, and inhibited proliferation of ZNF198-FGFR1 transformed Ba/F3 cells. Furthermore, treatment with PKC412 resulted in statistically significant prolongation of survival in the murine model of ZNF198-FGFR1-induced MPD. Based in part on these data, PKC412 was administered to a patient with t(8;13)(p11;q12) and was efficacious in treatment of progressive myeloproliferative disorder with organomegaly. Therefore, PKC412 may be a useful therapy for treatment of human stem cell leukemia-lymphoma syndrome.
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Demetri, G. D., von Mehren, M., Blanke, C. D., Van den Abbeele, A. D., Eisenberg, B., Roberts, P. J., Heinrich, M. C., Tuveson, D. A., Singer, S., Janicek, M., et al. (2002) · New England Journal of Medicine · doi:10.1056/nejmoa020461 · Cited by 4,389
Self-citationA common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome
Muenke, M., Schell, U., Hehr, A., Robin, N. H., Losken, H. W., Schinzel, A., Pulleyn, L. J., Rutland, P., Reardon, W., Malcolm, S., et al. (1994) · Nature Genetics · doi:10.1038/ng1194-269 · Cited by 614
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Hitosugi, T., Kang, S., Vander Heiden, M. G., Chung, T.-W., Elf, S., Lythgoe, K., Dong, S., Lonial, S., Wang, X., Chen, G. Z., et al. (2009) · Science Signaling · doi:10.1126/scisignal.2000431 · Cited by 784
Self-citationValent, P., Klion, A. D., Horny, H.-P., Roufosse, F., Gotlib, J., Weller, P. F., Hellmann, A., Metzgeroth, G., Leiferman, K. M., Arock, M., et al. (2012) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2012.02.019 · Cited by 767
Guagnano, V., Furet, P., Spanka, C., Bordas, V., Le Douget, M., Stamm, C., Brueggen, J., Jensen, M. R., Schnell, C., Schmid, H., et al. (2011) · Journal of Medicinal Chemistry · doi:10.1021/jm2006222 · Cited by 477
8p11 myeloproliferative syndrome: a review
Jackson, C. C., Medeiros, L. J., & Miranda, R. N. (2010) · Human Pathology · doi:10.1016/j.humpath.2009.11.003 · Cited by 247
Metadata
- Authors
- Chen, J., DeAngelo, D. J., Kutok, J. L., Williams, I. R., Lee, B. H., Wadleigh, M., Duclos, N., Cohen, S., Adelsperger, J., Okabe, R., Coburn, A., Galinsky, I., Huntly, B., Cohen, P. S., Meyer, T., Fabbro, D., Roesel, J., Banerji, L., Griffin, J. D., Xiao, S., Fletcher, J. A., Stone, R. M., & Gilliland, D. G.
- Venue
- Proceedings of the National Academy of Sciences
- Published
- 2004-09-24
- Volume
- 101
- Issue
- 40
- Pages
- 14479-14484
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- OpenAlex
- W2000893535
- Cited by
- 171
- References
- 2
- FWCI
- 9.25
- Type
- journal article
- Language
- en
- Open access
- green
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- Chen, J., DeAngelo, D. J., Kutok, J. L., Williams, I. R., Lee, B. H., Wadleigh, M., Duclos, N., Cohen, S., Adelsperger, J., Okabe, R., Coburn, A., Galinsky, I., Huntly, B., Cohen, P. S., Meyer, T., Fabbro, D., Roesel, J., Banerji, L., Griffin, J. D., . . . Gilliland, D. G. (2004). PKC412 inhibits the zinc finger 198-fibroblast growth factor receptor 1 fusion tyrosine kinase and is active in treatment of stem cell myeloproliferative disorder. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.0404438101
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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
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