Abstract
Most patients with acute lymphoblastic leukemia (ALL) fail current treatments highlighting the need for better therapies. Because oncogenic signaling activates a p53-dependent DNA damage response and apoptosis, leukemic cells must devise appropriate countermeasures. We show here that growth factor independence 1 (Gfi1) can serve such a function because Gfi1 ablation exacerbates p53 responses and lowers the threshold for p53-induced cell death. Specifically, Gfi1 restricts p53 activity and expression of proapoptotic p53 targets such as Bax, Noxa (Pmaip1), and Puma (Bbc3). Subsequently, Gfi1 ablation cures mice from leukemia and limits the expansion of primary human T-ALL xenografts in mice. This suggests that targeting Gfi1 could improve the prognosis of patients with T-ALL or other lymphoid leukemias.
Copyright © 2013 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis*
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DNA Damage / genetics*
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DNA-Binding Proteins / physiology*
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Humans
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Lymphoma, B-Cell / genetics
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Lymphoma, B-Cell / mortality
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Lymphoma, B-Cell / pathology*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mutation / genetics
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / mortality
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology*
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Receptor, Notch1 / genetics
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Transcription Factors / physiology*
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Tumor Suppressor Protein p53 / physiology*
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Xenograft Model Antitumor Assays
Substances
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DNA-Binding Proteins
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Gfi1 protein, mouse
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NOTCH1 protein, human
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Proto-Oncogene Proteins c-bcl-2
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Receptor, Notch1
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Transcription Factors
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Tumor Suppressor Protein p53