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

被引:227
作者
Chonghaile, Triona Ni [1 ]
Roderick, Justine E. [2 ]
Glenfield, Cian [3 ]
Ryan, Jeremy [1 ]
Sallan, Stephen E. [4 ]
Silverman, Lewis B. [4 ]
Loh, Mignon L. [5 ]
Hunger, Stephen P. [6 ,7 ]
Wood, Brent [8 ]
DeAngelo, Daniel J. [1 ]
Stone, Richard [1 ]
Harris, Marian [9 ]
Gutierrez, Alejandro [4 ,10 ]
Kelliher, Michelle A. [2 ]
Letai, Anthony [1 ]
机构
[1] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA
[2] Univ Massachusetts, Sch Med, Dept Canc Biol, Worcester, MA USA
[3] Trinity Coll Dublin, Smurfit Inst, Dept Genet, Dublin, Ireland
[4] Boston Childrens Hosp, Div Hematol Oncol, Boston, MA USA
[5] Univ Calif San Francisco, Dept Pediat, Benioff Childrens Hosp, San Francisco, CA USA
[6] Univ Colorado, Sch Med, Pediat Hematol Oncol BMT, Aurora, CO USA
[7] Childrens Hosp Colorado, Aurora, CO USA
[8] Univ Washington, Dept Med, Seattle, WA USA
[9] Boston Childrens Hosp, Dept Pathol, Boston, MA USA
[10] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA 02215 USA
关键词
CHRONIC LYMPHOCYTIC-LEUKEMIA; BH3; DOMAINS; ANTIAPOPTOTIC BCL-2; DEATH; BAX; EXPRESSION; INHIBITOR; MUTATIONS; APOPTOSIS; PROTEINS;
D O I
10.1158/2159-8290.CD-14-0353
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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. (C) 2014 AACR.
引用
收藏
页码:1074 / 1087
页数:14
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