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https://hdl.handle.net/2440/122368
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Type: | Journal article |
Title: | Bcl-2 is a therapeutic target for hypodiploid b-lineage acute lymphoblastic leukemia |
Author: | Diaz-Flores, E. Comeaux, E.Q. Kim, K.L. Melnik, E. Beckman, K. Davis, K.L. Wu, K. Akutagawa, J. Bridges, O. Marino, R. Wohlfeil, M. Braun, B.S. Mullighan, C.G. Loh, M.L. |
Citation: | Cancer Research, 2019; 79(9):2339-2351 |
Publisher: | American Association for Cancer Research |
Issue Date: | 2019 |
ISSN: | 0008-5472 1538-7445 |
Statement of Responsibility: | Ernesto Diaz-Flores, Evan Q. Comeaux, Kailyn L. Kim, Ella Melnik, Kyle Beckman, Kara L. Davis, Kevin Wu, Jon Akutagawa, Olga Bridges, Roberta Marino, Margo Wohlfeil, Benjamin S. Braun, Charles G. Mullighan and Mignon L. Loh |
Abstract: | Acute lymphoblastic leukemia (ALL) is the most common cancer in children. The highest rates of treatment failure occur in specific genetic subsets of ALL, including hypodiploid B-cell ALL (B-ALL), for which effective alternative therapies to current intensive chemotherapy treatments have yet to be developed. Here, we integrated biochemical and genomic profiling with functional drug assays to select effective agents with therapeutic potential against hypodiploid B-ALL. ABT-199, a selective Bcl-2 inhibitor, was effective in reducing leukemic burden in vitro and in vivo in patient-derived xenograft models of hypodiploid B-ALL. Daily oral treatment with ABT-199 significantly increased survival in xenografted mice. The unexpected efficacy of ABT-199 observed in hypodiploid leukemias lacking BIM expression (the major reported mediator of ABT-199-induced apoptosis) led us to investigate the mechanism of action of ABT-199 in the absence of BIM. Treatment with ABT-199 elicited responses in a dose-dependent manner, from cell-cycle arrest at low nanomolar concentrations to cell death at concentrations above 100 nmol/L. Collectively, these results demonstrate the efficacy of Bcl-2 inhibition and potential therapeutic strategy in hypodiploid B-ALL. SIGNIFICANCE: These results demonstrate the efficacy of ABT-199 in vivo and provide encouraging preclinical data of Bcl-2 as a potential target for the treatment of hypodiploid B-ALL. |
Keywords: | Tumor Cells, Cultured Animals Mice, Inbred NOD Humans Mice Mice, SCID Leukemia, Experimental Sulfonamides Proto-Oncogene Proteins c-bcl-2 Antineoplastic Agents Xenograft Model Antitumor Assays Apoptosis Cell Proliferation Cell Lineage Diploidy Precursor B-Cell Lymphoblastic Leukemia-Lymphoma Small Molecule Libraries Bridged Bicyclo Compounds, Heterocyclic |
Rights: | © 2019 American Association for Cancer Research |
DOI: | 10.1158/0008-5472.CAN-18-0236 |
Published version: | http://dx.doi.org/10.1158/0008-5472.can-18-0236 |
Appears in Collections: | Aurora harvest 8 Medicine publications |
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