title: Maturation stage of T-cell acute lymphoblastic leukemia determines BCL-2 versus BCL-XL dependence and sensitivity to ABT-199.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Triona Ni
authors.initials: TN
authors.lastname: Chonghaile
authors.affiliation: Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts.
authors.forename: Justine E
authors.initials: JE
authors.lastname: Roderick
authors.affiliation: Department of Genetics, The Smurfit Institute, Trinity College, Dublin, Ireland.
authors.forename: Cian
authors.initials: C
authors.lastname: Glenfield
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Ryan
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Sallan
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Lewis B
authors.initials: LB
authors.lastname: Silverman
authors.affiliation: Department of Pediatrics, Benioff Children's Hospital, University of California, San Francisco, San Francisco, California.
authors.forename: Mignon L
authors.initials: ML
authors.lastname: Loh
authors.affiliation: Pediatric Hematology/Oncology/BMT, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hunger
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington.
authors.forename: Brent
authors.initials: B
authors.lastname: Wood
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: DeAngelo
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Richard
authors.initials: R
authors.lastname: Stone
authors.affiliation: Department of Pathology, Boston Children's Hospital, Boston, Massachusetts.
authors.forename: Marian
authors.initials: M
authors.lastname: Harris
authors.affiliation: Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Gutierrez
authors.affiliation: Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts. anthony_letai@dfci.harvard.edu michelle.kelliher@umassmed.edu.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Kelliher
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. anthony_letai@dfci.harvard.edu michelle.kelliher@umassmed.edu.
authors.forename: Anthony
authors.initials: A
authors.lastname: Letai
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015870:Gene Expression; D006801:Humans; D008954:Models, Biological; D060787:Neoplasm Grading; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C474007:Bax protein (53-86); D019086:Bridged Bicyclo Compounds, Heterocyclic; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D051020:bcl-X Protein; C579720:venetoclax