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Cancer Discov. 2014 Sep;4(9):1074-87. doi: 10.1158/2159-8290.CD-14-0353. Epub 2014 Jul 3.

Maturation stage of T-cell acute lymphoblastic leukemia determines BCL-2 versus BCL-XL dependence and sensitivity to ABT-199.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
2
Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts.
3
Department of Genetics, The Smurfit Institute, Trinity College, Dublin, Ireland.
4
Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts.
5
Department of Pediatrics, Benioff Children's Hospital, University of California, San Francisco, San Francisco, California.
6
Pediatric Hematology/Oncology/BMT, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado.
7
Department of Medicine, University of Washington, Seattle, Washington.
8
Department of Pathology, Boston Children's Hospital, Boston, Massachusetts.
9
Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
10
Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts. anthony_letai@dfci.harvard.edu michelle.kelliher@umassmed.edu.
11
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. anthony_letai@dfci.harvard.edu michelle.kelliher@umassmed.edu.

Abstract

Acute lymphoblastic leukemia (ALL) is a hematopoietic malignancy derived from immature B-lymphoid and T-lymphoid cells (T-ALL). In T-ALL, there is an early T-cell progenitor (ETP) subgroup that has a very high risk for relapse. In this study, we used mitochondrial BH3 profiling to determine antiapoptotic protein dependencies in T-ALL. We found that T-ALL cell lines and primary patient samples are dependent upon BCL-XL, except when the cancer bears an ETP phenotype, in which case it is BCL-2 dependent. These distinctions directly relate to differential sensitivity to the BH3 mimetics ABT-263 and ABT-199, both in vitro and in vivo. We thus describe for the first time a change of antiapoptotic protein dependence that is related to the differentiation stage of the leukemic clone. Our findings demonstrate that BCL-2 is a clinically relevant target for therapeutic intervention with ABT-199 in ETP-ALL.

SIGNIFICANCE:

ETP T-ALL is a treatment-resistant subtype of T-ALL for which novel targeted therapies are urgently needed. We have discovered, through BH3 profiling, that ETP-ALL is BCL-2 dependent and is very sensitive to in vitro and in vivo treatment with ABT-199, a drug well tolerated in clinical trials.

PMID:
24994123
PMCID:
PMC4154982
DOI:
10.1158/2159-8290.CD-14-0353
[Indexed for MEDLINE]
Free PMC Article

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