title: Selective BCL-2 inhibition by ABT-199 causes on-target cell death in acute myeloid leukemia.
abstract: 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.
authors.affiliation: Departments of 1Leukemia, 2Pediatrics, and 3Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas; 4Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School; 5Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; 6The Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio; 7AbbVie Inc., North Chicago, Illinois; and 8Department of Laboratory Medicine, University of California San Francisco, San Francisco, California; 9Department of Internal Medicine III, University Hospital of Ulm, Ulm; 10MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: Rongqing
authors.initials: R
authors.lastname: Pan
authors.forename: Leah J
authors.initials: LJ
authors.lastname: Hogdal
authors.forename: Juliana M
authors.initials: JM
authors.lastname: Benito
authors.forename: Donna
authors.initials: D
authors.lastname: Bucci
authors.forename: Lina
authors.initials: L
authors.lastname: Han
authors.forename: Gautam
authors.initials: G
authors.lastname: Borthakur
authors.forename: Jorge
authors.initials: J
authors.lastname: Cortes
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: DeAngelo
authors.forename: Lakeisha
authors.initials: L
authors.lastname: Debose
authors.forename: Hong
authors.initials: H
authors.lastname: Mu
authors.forename: Hartmut
authors.initials: H
authors.lastname: Döhner
authors.forename: Verena I
authors.initials: VI
authors.lastname: Gaidzik
authors.forename: Ilene
authors.initials: I
authors.lastname: Galinsky
authors.forename: Leonard S
authors.initials: LS
authors.lastname: Golfman
authors.forename: Torsten
authors.initials: T
authors.lastname: Haferlach
authors.forename: Karine G
authors.initials: KG
authors.lastname: Harutyunyan
authors.forename: Jianhua
authors.initials: J
authors.lastname: Hu
authors.forename: Joel D
authors.initials: JD
authors.lastname: Leverson
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.forename: Markus
authors.initials: M
authors.lastname: Müschen
authors.forename: Rachel
authors.initials: R
authors.lastname: Newman
authors.forename: Eugene
authors.initials: E
authors.lastname: Park
authors.forename: Peter P
authors.initials: PP
authors.lastname: Ruvolo
authors.forename: Vivian
authors.initials: V
authors.lastname: Ruvolo
authors.forename: Jeremy
authors.initials: J
authors.lastname: Ryan
authors.forename: Sonja
authors.initials: S
authors.lastname: Schindela
authors.forename: Patrick
authors.initials: P
authors.lastname: Zweidler-McKay
authors.forename: Richard M
authors.initials: RM
authors.lastname: Stone
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.forename: Michael
authors.initials: M
authors.lastname: Andreeff
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
authors.forename: Anthony G
authors.initials: AG
authors.lastname: Letai
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor; D001713:Biphenyl Compounds / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D009374:Neoplasms, Experimental; D009596:Nitrophenols / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: C501332:ABT-737; D000814:Aniline Compounds; D000970:Antineoplastic Agents; C474007:Bax protein (53-86); D014408:Biomarkers, Tumor; D001713:Biphenyl Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D009596:Nitrophenols; D010446:Peptide Fragments; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; C579720:venetoclax; C528561:navitoclax