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Oncotarget. 2016 Mar 8;7(10):11500-11. doi: 10.18632/oncotarget.7204.

Defining specificity and on-target activity of BH3-mimetics using engineered B-ALL cell lines.

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Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Adult Oncology, The Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Integrated Program in Biomedical Sciences, University of Tennessee Health Science Center, Memphis, TN, USA.
Eutropics Incorporated, Cambridge, MA, USA.
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.


One of the hallmarks of cancer is a resistance to the induction of programmed cell death that is mediated by selection of cells with elevated expression of anti-apoptotic members of the BCL-2 family. To counter this resistance, new therapeutic agents known as BH3-mimetic small molecules are in development with the goal of antagonizing the function of anti-apoptotic molecules and promoting the induction of apoptosis. To facilitate the testing and modeling of BH3-mimetic agents, we have developed a powerful system for evaluation and screening of agents both in culture and in immune competent animal models by engineering mouse leukemic cells and re-programming them to be dependent on exogenously expressed human anti-apoptotic BCL-2 family members. Here we demonstrate that this panel of cell lines can determine the specificity of BH3-mimetics to individual anti-apoptotic BCL-2 family members (BCL-2, BCL-XL, BCL-W, BFL-1, and MCL-1), demonstrate whether cell death is due to the induction of apoptosis (BAX and BAK-dependent), and faithfully assess the efficacy of BH3-mimetic small molecules in pre-clinical mouse models. These cells represent a robust and valuable pre-clinical screening tool for validating the efficacy, selectivity, and on-target action of BH3-mimetic agents.


BCL-2; BH3 mimetics; apoptosis; cancer model; drug development

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