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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.

Original publication

DOI

10.1182/blood-2014-05-574566

Type

Journal article

Journal

Blood

Publication Date

11/12/2014

Volume

124

Pages

3738 - 3747

Keywords

Animals, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Blotting, Western, Bridged Bicyclo Compounds, Heterocyclic, Cell Line, Tumor, Cell Survival, Cells, Cultured, Child, Drug Synergism, Gene Expression Profiling, Gene Expression Regulation, Leukemic, HEK293 Cells, Humans, Inhibitory Concentration 50, Jurkat Cells, Mice, Inbred NOD, Mice, SCID, Oligonucleotide Array Sequence Analysis, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Proto-Oncogene Proteins c-bcl-2, Reverse Transcriptase Polymerase Chain Reaction, Sulfonamides, Survival Analysis, Tumor Cells, Cultured, Xenograft Model Antitumor Assays