Targeting BET proteins improves the therapeutic efficacy of BCL-2 inhibition in T-cell acute lymphoblastic leukemia

S Peirs; V Frismantas; F Matthijssens; W Van Loocke; T Pieters; N Vandamme; B Lintermans; M P Dobay; G Berx; B Poppe; S Goossens; B C Bornhauser; J-P Bourquin; P Van Vlierberghe

doi:10.1038/leu.2017.10

Targeting BET proteins improves the therapeutic efficacy of BCL-2 inhibition in T-cell acute lymphoblastic leukemia

Leukemia. 2017 Oct;31(10):2037-2047. doi: 10.1038/leu.2017.10. Epub 2017 Jan 11.

Authors

S Peirs^{1

2}, V Frismantas³, F Matthijssens^{1

2}, W Van Loocke^{1

2}, T Pieters^{1

2

4

5}, N Vandamme^{2

4

5}, B Lintermans^{1

2}, M P Dobay⁶, G Berx^{2

4

5}, B Poppe^{1

2}, S Goossens^{1

2

4

5}, B C Bornhauser³, J-P Bourquin³, P Van Vlierberghe^{1

2}

Affiliations

¹ Center for Medical Genetics, Ghent University, Ghent, Belgium.
² Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
³ Department of Pediatric Oncology, Children's Research Centre, University Children's Hospital Zurich, Zurich, Switzerland.
⁴ Molecular and Cellular Oncology Lab, VIB Inflammation Research Center, Ghent University, Ghent, Belgium.
⁵ Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
⁶ Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.

PMID: 28074072
DOI: 10.1038/leu.2017.10

Abstract

Inhibition of anti-apoptotic BCL-2 (B-cell lymphoma 2) has recently emerged as a promising new therapeutic strategy for the treatment of a variety of human cancers, including leukemia. Here, we used T-cell acute lymphoblastic leukemia (T-ALL) as a model system to identify novel synergistic drug combinations with the BH3 mimetic venetoclax (ABT-199). In vitro drug screening in primary leukemia specimens that were derived from patients with high risk of relapse or relapse and cell lines revealed synergistic activity between venetoclax and the BET (bromodomain and extraterminal) bromodomain inhibitor JQ1. Notably, this drug synergism was confirmed in vivo using T-ALL cell line and patient-derived xenograft models. Moreover, the therapeutic benefit of this drug combination might, at least in part, be mediated by an acute induction of the pro-apoptotic factor BCL2L11 and concomitant reduction of BCL-2 upon BET bromodomain inhibition, ultimately resulting in an enhanced binding of BIM (encoded by BCL2L11) to BCL-2. Altogether, our work provides a rationale to develop a new type of targeted combination therapy for selected subgroups of high-risk leukemia patients.

Publication types

Comparative Study

MeSH terms

Animals
Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
Azepines / administration & dosage
Azepines / pharmacology*
Bcl-2-Like Protein 11 / biosynthesis
Bcl-2-Like Protein 11 / genetics
Bridged Bicyclo Compounds, Heterocyclic / administration & dosage
Bridged Bicyclo Compounds, Heterocyclic / pharmacology*
Cell Cycle Proteins
Cell Line, Tumor
Drug Synergism
Female
Gene Expression Regulation, Neoplastic / drug effects
Humans
Mice
Mice, Inbred NOD
Mice, SCID
Molecular Targeted Therapy*
Neoplasm Proteins / antagonists & inhibitors*
Neoplasm Proteins / biosynthesis
Neoplasm Proteins / genetics
Nuclear Proteins / antagonists & inhibitors
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*
Protein Domains
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
Sulfonamides / administration & dosage
Sulfonamides / pharmacology*
Transcription Factors / antagonists & inhibitors
Triazoles / administration & dosage
Triazoles / pharmacology*
Xenograft Model Antitumor Assays

Substances

(+)-JQ1 compound
Azepines
BCL2L11 protein, human
BRD4 protein, human
Bcl-2-Like Protein 11
Bridged Bicyclo Compounds, Heterocyclic
Cell Cycle Proteins
Neoplasm Proteins
Nuclear Proteins
Proto-Oncogene Proteins c-bcl-2
Sulfonamides
Transcription Factors
Triazoles
venetoclax