title: Defining specificity and on-target activity of BH3-mimetics using engineered B-ALL cell lines.
abstract: 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.
authors: Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors: Brian
authors: B
authors: Koss
authors: Department of Adult Oncology, The Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors: Jeremy
authors: J
authors: Ryan
authors: Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors: Amit
authors: A
authors: Budhraja
authors: Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors: Katherine
authors: K
authors: Szarama
authors: Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.|Integrated Program in Biomedical Sciences, University of Tennessee Health Science Center, Memphis, TN, USA.
authors: Xue
authors: X
authors: Yang
authors: Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors: Madhavi
authors: M
authors: Bathina
authors: Eutropics Incorporated, Cambridge, MA, USA.
authors: Michael H
authors: MH
authors: Cardone
authors: Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
authors: Zaneta
authors: Z
authors: Nikolovska-Coleska
authors: Department of Adult Oncology, The Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors: Anthony
authors: A
authors: Letai
authors: Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors: Joseph T
authors: JT
authors: Opferman
mesh_terms: D000818:Animals; D017209:Apoptosis; D040761:Biomimetic Materials / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism*; D054852:Small Molecule Libraries / Q000494:pharmacology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C474007:Bax protein (53-86); D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D054852:Small Molecule Libraries
keywords: BCL-2; BH3 mimetics; apoptosis; cancer model; drug development