Epigenetic regulation of the Ink4a-Arf (Cdkn2a) tumor suppressor locus in the initiation and progression of Notch1-driven T cell acute lymphoblastic leukemia.

Volanakis EJ, Boothby MR, Sherr CJ
Exp Hematol. 2013 41 (4): 377-86

PMID: 23178376 · PMCID: PMC3860824 · DOI:10.1016/j.exphem.2012.11.006

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.

MeSH Terms (25)

Animals Binding Sites Bone Marrow Cells Cell Line Cells, Cultured Cell Transformation, Neoplastic Coculture Techniques Cyclin-Dependent Kinase Inhibitor p16 Disease Progression Dogs Epigenesis, Genetic Flow Cytometry Gene Expression Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Mutation Precursor T-Cell Lymphoblastic Leukemia-Lymphoma Receptor, Notch1 Reverse Transcriptase Polymerase Chain Reaction Signal Transduction T-Lymphocytes Thymocytes Tumor Suppressor Protein p14ARF

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