title: BH3 Inhibitor Sensitivity and Bcl-2 Dependence in Primary Acute Lymphoblastic Leukemia Cells.
abstract: BH3 mimetic drugs may be useful to treat acute lymphoblastic leukemia (ALL) but the sensitivity of primary tumor cells has not been fully evaluated. Here, B-lineage ALL cell cultures derived from a set of primary tumors were studied with respect to sensitivity to the BH3 mimetics ABT-263 and ABT-199 and to Bcl-2 dependence and function. These ALL cells each expressed high levels of Bcl-2 and exhibited great sensitivity to ABT-263 and ABT-199, which induced rapid apoptotic cell death. BH3 profiling indicated that the ALL cultures were Bcl-2 dependent. Coimmunoprecipitation studies revealed a multifaceted role for Bcl-2 in binding proapoptotic partners including Bax, Bak, Bik, and Bim. ABT-263 disrupted Bcl-2:Bim interaction in cells. Mcl-1 overexpression rendered ALL cells resistant to ABT-263 and ABT-199, with Mcl-1 assuming the role of Bcl-2 in binding Bim. Freshly isolated pediatric ALL blasts also expressed high levels of Bcl-2 and exhibited high sensitivity to Bcl-2 inhibition by the BH3 mimetic compounds. Overall, our results showed that primary ALL cultures were both more sensitive to BH3 mimetics and more uniform in their response than established ALL cell lines that have been evaluated previously. Furthermore, the primary cell model characterized here offers a powerful system for preclinical testing of novel drugs and drug combinations to treat ALL.
authors: Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors: Sarah E
authors: SE
authors: Alford
authors: Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors: Anisha
authors: A
authors: Kothari
authors: Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands.
authors: Floris C
authors: FC
authors: Loeff
authors: Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors: Joshua M
authors: JM
authors: Eichhorn
authors: Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors: Nandini
authors: N
authors: Sakurikar
authors: Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands.
authors: Henriette M
authors: HM
authors: Goselink
authors: Department of Pediatrics, Section of Pediatric Hematology-Oncology, University of Arkansas for Medical Sciences at Arkansas Children's Hospital, Little Rock, Arkansas.
authors: Robert L
authors: RL
authors: Saylors
authors: Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands.
authors: Inge
authors: I
authors: Jedema
authors: Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands.
authors: J H Frederik
authors: JH
authors: Falkenburg
authors: Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, Arkansas. chamberstimothyc@uams.edu.
authors: Timothy C
authors: TC
authors: Chambers
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D000814:Aniline Compounds; D000970:Antineoplastic Agents; C000595707:BCL2 protein, human; D019086:Bridged Bicyclo Compounds, Heterocyclic; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; C579720:venetoclax; C528561:navitoclax
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