1. ABT-199 mediated inhibition of BCL-2 as a novel therapeutic strategy in T-cell acute lymphoblastic leukemia.
- Author
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Peirs S, Matthijssens F, Goossens S, Van de Walle I, Ruggero K, de Bock CE, Degryse S, Canté-Barrett K, Briot D, Clappier E, Lammens T, De Moerloose B, Benoit Y, Poppe B, Meijerink JP, Cools J, Soulier J, Rabbitts TH, Taghon T, Speleman F, and Van Vlierberghe P
- Subjects
- Animals, Antineoplastic Agents administration & dosage, Antineoplastic Combined Chemotherapy Protocols pharmacology, Blotting, Western, Bridged Bicyclo Compounds, Heterocyclic administration & dosage, 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 genetics, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma metabolism, Proto-Oncogene Proteins c-bcl-2 genetics, Proto-Oncogene Proteins c-bcl-2 metabolism, Reverse Transcriptase Polymerase Chain Reaction, Sulfonamides administration & dosage, Survival Analysis, Tumor Cells, Cultured, Bridged Bicyclo Compounds, Heterocyclic pharmacology, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Proto-Oncogene Proteins c-bcl-2 antagonists & inhibitors, Sulfonamides pharmacology, Xenograft Model Antitumor Assays
- 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., (© 2014 by The American Society of Hematology.)
- Published
- 2014
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