title: Epigenetic regulation of the Ink4a-Arf (Cdkn2a) tumor suppressor locus in the initiation and progression of Notch1-driven T cell acute lymphoblastic leukemia.
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.
authors.affiliation: Division of Pediatric Hematology-Oncology, Vanderbilt University, Nashville, TN, USA. emmanuel.volanakis@vanderbilt.edu
authors.forename: Emmanuel J
authors.initials: EJ
authors.lastname: Volanakis
authors.forename: Mark R
authors.initials: MR
authors.lastname: Boothby
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Sherr
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000235:genetics; D001854:Bone Marrow Cells / Q000166:cytology / Q000378:metabolism; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D018920:Coculture Techniques; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D018450:Disease Progression; D004285:Dogs; D044127:Epigenesis, Genetic; D005434:Flow Cytometry; D015870:Gene Expression; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051881:Receptor, Notch1 / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D060168:Thymocytes / Q000166:cytology / Q000378:metabolism; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics* / Q000378:metabolism
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D051881:Receptor, Notch1; D025803:Tumor Suppressor Protein p14ARF