Abstract
Activating mutations of NOTCH1 and deletion of the INK4A-ARF (CDKN2A) tumor suppressor locus are two of the most frequent genetic alterations in T cell acute lymphoblastic leukemia (T-ALL). In a murine model of T-ALL induced by the intracellular domain of Notch1 (ICN1), the genetic interaction between ICN1 signaling and Arf inactivation is developmentally stage-specific, with a more pronounced requirement for Arf deletion in thymocytes than in bone marrow precursors targeted for transformation. In the thymus, the target cell for transformation is a CD4 and CD8 double-negative progenitor that undergoes T cell receptor beta-chain rearrangement, a cell type in which polycomb silencing of Ink4a-Arf is normally requisite. Epigenetic remodeling during tumor progression licenses Arf as a tumor suppressor and in turn provides the selective pressure for Ink4a-Arf deletion in clonal T-ALLs that emerge.
Copyright © 2013 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Binding Sites / genetics
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Bone Marrow Cells / cytology
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Bone Marrow Cells / metabolism
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Cell Line
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Cell Transformation, Neoplastic / genetics
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Cells, Cultured
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Coculture Techniques
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Cyclin-Dependent Kinase Inhibitor p16 / genetics*
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Cyclin-Dependent Kinase Inhibitor p16 / metabolism
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Disease Progression
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Dogs
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Epigenesis, Genetic
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Flow Cytometry
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Gene Expression
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Mutation
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics*
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
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Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / pathology
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Receptor, Notch1 / genetics*
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Receptor, Notch1 / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / genetics
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T-Lymphocytes / cytology
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T-Lymphocytes / metabolism
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Thymocytes / cytology
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Thymocytes / metabolism
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Tumor Suppressor Protein p14ARF / genetics*
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Tumor Suppressor Protein p14ARF / metabolism
Substances
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Cyclin-Dependent Kinase Inhibitor p16
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Receptor, Notch1
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Tumor Suppressor Protein p14ARF