Title: ABT-199 mediated inhibition of BCL-2 as a novel therapeutic strategy in T-cell acute lymphoblastic leukemia
Authors: Peirs, Sofie
Matthijssens, Filip
Goossens, Steven
Van de Walle, Inge
Ruggero, Katia
De Bock, Charles
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 # ×
Issue Date: Dec-2014
Publisher: W.B. Saunders
Series Title: Blood vol:124 issue:25 pages:3738-47
Article number: 10.1182/blood-2014-05-574566
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.
ISSN: 0006-4971
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Laboratory of Molecular Biology of Leukemia
× corresponding author
# (joint) last author

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