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

  • Blood. 2014 Dec 11;124(25):3738-47. doi: 10.1182/blood-2014-05-574566.
Sofie Peirs  1 ,  Filip Matthijssens  1 ,  Steven Goossens  2 ,  Inge Van de Walle  3 ,  Katia Ruggero  4 ,  Charles E de Bock  5 ,  Sandrine Degryse  5 ,  Kirsten Canté-Barrett  6 ,  Delphine Briot  7 ,  Emmanuelle Clappier  7 ,  Tim Lammens  8 ,  Barbara De Moerloose  8 ,  Yves Benoit  8 ,  Bruce Poppe  1 ,  Jules P Meijerink  6 ,  Jan Cools  5 ,  Jean Soulier  7 ,  Terence H Rabbitts  4 ,  Tom Taghon  3 ,  Frank Speleman  1 ,  Pieter Van Vlierberghe  1
Affiliations
  • 1. Center for Medical Genetics.
  • 2. Flanders Institute for Biotechnology Inflammation Research Center, and.
  • 3. Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, Ghent, Belgium;
  • 4. Medical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, England, United Kingdom;
  • 5. Laboratory for the Molecular Biology of Leukemia, Center for Human Genetics, University of Leuven and Center for the Biology of Disease, Vlaams Instituut voor Biotechnologie, Leuven, Belgium;
  • 6. Department of Pediatric Oncology/Hematology, Erasmus Medical Center, Rotterdam, The Netherlands;
  • 7. Genome Rearrangements and Cancer Laboratory, U462 INSERM, Laboratoire Central d'Hématologie and Institut Universitaire d'Hématologie, Hopital Saint-Louis, Paris, France; and.
  • 8. Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium.
PMID: 25301704 DOI: 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.

Products