期刊
CANCER DISCOVERY
卷 4, 期 9, 页码 1074-1087出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-14-0353
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资金
- NIH/National Cancer Institute [CA167124]
- NCI [U10 CA98543, U10 CA98413, U24 CA114766]
- American Cancer Society Post-Doctoral Fellowship [125087-PF-13-247-01-LIB]
- NIH/NCI [CA096899, R01 CA129974]
- William Lawrence and Blanche Hughes Foundation
- Linde Family Foundation
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.
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