title: ABT-199 mediated inhibition of BCL-2 as a novel therapeutic strategy in T-cell acute lymphoblastic leukemia.
abstract: T-cell acute lymphoblastic leukemia (T-ALL) is a high-risk subtype of acute lymphoblastic leukemia (ALL) with gradually improved survival through introduction of intensified chemotherapy. However, therapy-resistant or refractory T-ALL remains a major clinical challenge. Here, we evaluated B-cell lymphoma (BCL)-2 inhibition by the BH3 mimetic ABT-199 as a new therapeutic strategy in human T-ALL. The T-ALL cell line LOUCY, which shows a transcriptional program related to immature T-ALL, exhibited high in vitro and in vivo sensitivity for ABT-199 in correspondence with high levels of BCL-2. In addition, ABT-199 showed synergistic therapeutic effects with different chemotherapeutic agents including doxorubicin, l-asparaginase, and dexamethasone. Furthermore, in vitro analysis of primary patient samples indicated that some immature, TLX3- or HOXA-positive primary T-ALLs are highly sensitive to BCL-2 inhibition, whereas TAL1 driven tumors mostly showed poor ABT-199 responses. Because BCL-2 shows high expression in early T-cell precursors and gradually decreases during normal T-cell differentiation, differences in ABT-199 sensitivity could partially be mediated by distinct stages of differentiation arrest between different molecular genetic subtypes of human T-ALL. In conclusion, our study highlights BCL-2 as an attractive molecular target in specific subtypes of human T-ALL that could be exploited by ABT-199.
authors.affiliation: Center for Medical Genetics.
authors.forename: Sofie
authors.initials: S
authors.lastname: Peirs
authors.affiliation: Center for Medical Genetics.
authors.forename: Filip
authors.initials: F
authors.lastname: Matthijssens
authors.affiliation: Flanders Institute for Biotechnology Inflammation Research Center, and.
authors.forename: Steven
authors.initials: S
authors.lastname: Goossens
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium;
authors.forename: Inge
authors.initials: I
authors.lastname: Van de Walle
authors.affiliation: Medical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, England, United Kingdom;
authors.forename: Katia
authors.initials: K
authors.lastname: Ruggero
authors.affiliation: Laboratory for the Molecular Biology of Leukemia, Center for Human Genetics, University of Leuven and Center for the Biology of Disease, Vlaams Instituut voor Biotechnologie, Leuven, Belgium;
authors.forename: Charles E
authors.initials: CE
authors.lastname: de Bock
authors.affiliation: Laboratory for the Molecular Biology of Leukemia, Center for Human Genetics, University of Leuven and Center for the Biology of Disease, Vlaams Instituut voor Biotechnologie, Leuven, Belgium;
authors.forename: Sandrine
authors.initials: S
authors.lastname: Degryse
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus Medical Center, Rotterdam, The Netherlands;
authors.forename: Kirsten
authors.initials: K
authors.lastname: Canté-Barrett
authors.affiliation: Genome Rearrangements and Cancer Laboratory, U462 INSERM, Laboratoire Central d'Hématologie and Institut Universitaire d'Hématologie, Hopital Saint-Louis, Paris, France; and.
authors.forename: Delphine
authors.initials: D
authors.lastname: Briot
authors.affiliation: Genome Rearrangements and Cancer Laboratory, U462 INSERM, Laboratoire Central d'Hématologie and Institut Universitaire d'Hématologie, Hopital Saint-Louis, Paris, France; and.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Clappier
authors.affiliation: Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium.
authors.forename: Tim
authors.initials: T
authors.lastname: Lammens
authors.affiliation: Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium.
authors.forename: Barbara
authors.initials: B
authors.lastname: De Moerloose
authors.affiliation: Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium.
authors.forename: Yves
authors.initials: Y
authors.lastname: Benoit
authors.affiliation: Center for Medical Genetics.
authors.forename: Bruce
authors.initials: B
authors.lastname: Poppe
authors.affiliation: Department of Pediatric Oncology/Hematology, Erasmus Medical Center, Rotterdam, The Netherlands;
authors.forename: Jules P
authors.initials: JP
authors.lastname: Meijerink
authors.affiliation: Laboratory for the Molecular Biology of Leukemia, Center for Human Genetics, University of Leuven and Center for the Biology of Disease, Vlaams Instituut voor Biotechnologie, Leuven, Belgium;
authors.forename: Jan
authors.initials: J
authors.lastname: Cools
authors.affiliation: Genome Rearrangements and Cancer Laboratory, U462 INSERM, Laboratoire Central d'Hématologie and Institut Universitaire d'Hématologie, Hopital Saint-Louis, Paris, France; and.
authors.forename: Jean
authors.initials: J
authors.lastname: Soulier
authors.affiliation: Medical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, England, United Kingdom;
authors.forename: Terence H
authors.initials: TH
authors.lastname: Rabbitts
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium;
authors.forename: Tom
authors.initials: T
authors.lastname: Taghon
authors.affiliation: Center for Medical Genetics.
authors.forename: Frank
authors.initials: F
authors.lastname: Speleman
authors.affiliation: Center for Medical Genetics.
authors.forename: Pieter
authors.initials: P
authors.lastname: Van Vlierberghe
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D015153:Blotting, Western; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002648:Child; D004357:Drug Synergism; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D019169:Jurkat Cells; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D020411:Oligonucleotide Array Sequence Analysis; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology*; D016019:Survival Analysis; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; C579720:venetoclax