The DOI matches its Crossref record; 3 of the 3 references it cites were found in a registry or an index.
Selective BCL-2 Inhibition by ABT-199 Causes On-Target Cell Death in Acute Myeloid Leukemia
Open accessAbstract
B-cell leukemia/lymphoma 2 (BCL-2) prevents commitment to programmed cell death at the mitochondrion. It remains a challenge to identify those tumors that are best treated by inhibition of BCL-2. Here, we demonstrate that acute myeloid leukemia (AML) cell lines, primary patient samples, and murine primary xenografts are very sensitive to treatment with the selective BCL-2 antagonist ABT-199. In primary patient cells, the median IC50 was approximately 10 nmol/L, and cell death occurred within 2 hours. Our ex vivo sensitivity results compare favorably with those observed for chronic lymphocytic leukemia, a disease for which ABT-199 has demonstrated consistent activity in clinical trials. Moreover, mitochondrial studies using BH3 profiling demonstrate activity at the mitochondrion that correlates well with cytotoxicity, supporting an on-target mitochondrial mechanism of action. Our protein and BH3 profiling studies provide promising tools that can be tested as predictive biomarkers in any clinical trial of ABT-199 in AML. Significance: Although targeting BCL-2 has largely been investigated in lymphoid cancers, we present preclinical results of targeting BCL-2 in AML. These results support clinical testing of the small-molecule BCL-2 antagonist ABT-199 in AML, accompanied by testing of predictive biomarkers used in this study. Cancer Discov; 4(3); 362–75. ©2013 AACR. See related commentary by Hockenbery, p. 278 This article is highlighted in the In This Issue feature, p. 259
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Self-citationGandhi, L., Camidge, D. R., Ribeiro de Oliveira, M., Bonomi, P., Gandara, D., Khaira, D., Hann, C. L., McKeegan, E. M., Litvinovich, E., Hemken, P. M., et al. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2010.31.6208 · Cited by 603
Schoenwaelder, S. M., Jarman, K. E., Gardiner, E. E., Hua, M., Qiao, J., White, M. J., Josefsson, E. C., Alwis, I., Ono, A., Willcox, A., et al. (2011) · Blood · doi:10.1182/blood-2011-04-347849 · Cited by 351
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Metadata
- Authors
- Pan, R., Hogdal, L. J., Benito, J. M., Bucci, D., Han, L., Borthakur, G., Cortes, J., DeAngelo, D. J., Debose, L., Mu, H., Döhner, H., Gaidzik, V. I., Galinsky, I., Golfman, L. S., Haferlach, T., Harutyunyan, K. G., Hu, J., Leverson, J. D., Marcucci, G., Müschen, M., Newman, R., Park, E., Ruvolo, P. P., Ruvolo, V., Ryan, J., Schindela, S., Zweidler-McKay, P., Stone, R. M., Kantarjian, H., Andreeff, M., Konopleva, M., & Letai, A. G.
- Venue
- Cancer Discovery
- Published
- 2014-03-01
- Volume
- 4
- Issue
- 3
- Pages
- 362-375
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- OpenAlex
- W2102461774
- Cited by
- 735
- References
- 3
- FWCI
- 13.31
- Type
- journal article
- Language
- en
- Open access
- green
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- The paper
- Pan, R., Hogdal, L. J., Benito, J. M., Bucci, D., Han, L., Borthakur, G., Cortes, J., DeAngelo, D. J., Debose, L., Mu, H., Döhner, H., Gaidzik, V. I., Galinsky, I., Golfman, L. S., Haferlach, T., Harutyunyan, K. G., Hu, J., Leverson, J. D., Marcucci, G., . . . Letai, A. G. (2014). Selective BCL-2 Inhibition by ABT-199 Causes On-Target Cell Death in Acute Myeloid Leukemia. Cancer Discovery. https://doi.org/10.1158/2159-8290.cd-13-0609
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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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