ABT-199 mediated inhibition of BCL-2 as a novel therapeutic strategy in T-cell acute lymphoblastic leukemia

• Published in: Blood Vol. 124; no. 25; pp. 3738 - 3747
• Main Authors: Peirs, Sofie, Matthijssens, Filip, Goossens, Steven, Van de Walle, Inge, Ruggero, Katia, de Bock, Charles E., Degryse, Sandrine, Canté-Barrett, Kirsten, Briot, Delphine, Clappier, Emmanuelle, Lammens, Tim, De Moerloose, Barbara, Benoit, Yves, Poppe, Bruce, Meijerink, Jules P., Cools, Jan, Soulier, Jean, Rabbitts, Terence H., Taghon, Tom, Speleman, Frank, Van Vlierberghe, Pieter
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 11.12.2014
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Blotting, Western; Bridged Bicyclo Compounds, Heterocyclic - administration & dosage; Bridged Bicyclo Compounds, Heterocyclic - pharmacology; Cell Line, Tumor; Cell Survival - drug effects; Cell Survival - genetics; Cells, Cultured; Child; Drug Synergism; Gene Expression Profiling; Gene Expression Regulation, Leukemic - drug effects; HEK293 Cells; Humans; Inhibitory Concentration 50; Jurkat Cells; Mice, Inbred NOD; Mice, SCID; Oligonucleotide Array Sequence Analysis; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Proto-Oncogene Proteins c-bcl-2 - genetics; Proto-Oncogene Proteins c-bcl-2 - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Sulfonamides - administration & dosage; Sulfonamides - pharmacology; Survival Analysis; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2014-05-574566

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. •High levels of the anti-apoptotic factor BCL-2 can be therapeutically exploited by the BH3 mimetic ABT-199 in human T-ALL.