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Cancer Discovery
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Maturation Stage of T-cell Acute Lymphoblastic Leukemia Determines BCL-2 versus BCL-XL Dependence and Sensitivity to ABT-199

Triona Ni Chonghaile, Justine E. Roderick, Cian Glenfield, Jeremy Ryan, Stephen E. Sallan, Lewis B. Silverman, Mignon L. Loh, Stephen P. Hunger, Brent Wood, Daniel J. DeAngelo, Richard Stone, Marian Harris, Alejandro Gutierrez, Michelle A. Kelliher and Anthony Letai
Triona Ni Chonghaile
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Justine E. Roderick
2Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts.
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Cian Glenfield
3Department of Genetics, The Smurfit Institute, Trinity College, Dublin, Ireland.
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Jeremy Ryan
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Stephen E. Sallan
4Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts.
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Lewis B. Silverman
4Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts.
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Mignon L. Loh
5Department of Pediatrics, Benioff Children's Hospital, University of California, San Francisco, San Francisco, California.
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Stephen P. Hunger
6Pediatric Hematology/Oncology/BMT, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado.
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Brent Wood
7Department of Medicine, University of Washington, Seattle, Washington.
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Daniel J. DeAngelo
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Richard Stone
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Marian Harris
8Department of Pathology, Boston Children's Hospital, Boston, Massachusetts.
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Alejandro Gutierrez
4Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts.
9Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
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Michelle A. Kelliher
2Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts.
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  • For correspondence: anthony_letai@dfci.harvard.edu michelle.kelliher@umassmed.edu
Anthony Letai
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
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  • For correspondence: anthony_letai@dfci.harvard.edu michelle.kelliher@umassmed.edu
DOI: 10.1158/2159-8290.CD-14-0353 Published September 2014
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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. Cancer Discov; 4(9); 1074–87. ©2014 AACR.

This article is highlighted in the In This Issue feature, p. 973

Footnotes

  • Note: Supplementary data for this article are available at Cancer Discovery Online (http://cancerdiscovery.aacrjournals.org/).

  • Received April 4, 2014.
  • Revision received July 2, 2014.
  • Accepted July 2, 2014.
  • ©2014 American Association for Cancer Research.
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Cancer Discovery: 4 (9)
September 2014
Volume 4, Issue 9
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Maturation Stage of T-cell Acute Lymphoblastic Leukemia Determines BCL-2 versus BCL-XL Dependence and Sensitivity to ABT-199
Triona Ni Chonghaile, Justine E. Roderick, Cian Glenfield, Jeremy Ryan, Stephen E. Sallan, Lewis B. Silverman, Mignon L. Loh, Stephen P. Hunger, Brent Wood, Daniel J. DeAngelo, Richard Stone, Marian Harris, Alejandro Gutierrez, Michelle A. Kelliher and Anthony Letai
Cancer Discov September 1 2014 (4) (9) 1074-1087; DOI: 10.1158/2159-8290.CD-14-0353

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Maturation Stage of T-cell Acute Lymphoblastic Leukemia Determines BCL-2 versus BCL-XL Dependence and Sensitivity to ABT-199
Triona Ni Chonghaile, Justine E. Roderick, Cian Glenfield, Jeremy Ryan, Stephen E. Sallan, Lewis B. Silverman, Mignon L. Loh, Stephen P. Hunger, Brent Wood, Daniel J. DeAngelo, Richard Stone, Marian Harris, Alejandro Gutierrez, Michelle A. Kelliher and Anthony Letai
Cancer Discov September 1 2014 (4) (9) 1074-1087; DOI: 10.1158/2159-8290.CD-14-0353
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