PT  - JOURNAL ARTICLE
AU  - Chonghaile, Triona Ni
AU  - Roderick, Justine E.
AU  - Glenfield, Cian
AU  - Ryan, Jeremy
AU  - Sallan, Stephen E.
AU  - Silverman, Lewis B.
AU  - Loh, Mignon L.
AU  - Hunger, Stephen P.
AU  - Wood, Brent
AU  - DeAngelo, Daniel J.
AU  - Stone, Richard
AU  - Harris, Marian
AU  - Gutierrez, Alejandro
AU  - Kelliher, Michelle A.
AU  - Letai, Anthony
TI  - Maturation Stage of T-cell Acute Lymphoblastic Leukemia Determines BCL-2 versus BCL-XL Dependence and Sensitivity to ABT-199
AID  - 10.1158/2159-8290.CD-14-0353
DP  - 2014 Sep 01
TA  - Cancer Discovery
PG  - 1074--1087
VI  - 4
IP  - 9
4099  - http://cancerdiscovery.aacrjournals.org/content/4/9/1074.short
4100  - http://cancerdiscovery.aacrjournals.org/content/4/9/1074.full
SO  - CANCER DISCOVERY2014 Sep 01; 4
AB  - 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