Abstract
Acute Lymphoblastic Leukemia (ALL) non-random fusions influence clinical outcome and alter the accumulation of MTX-PGs in vivo. Analysis of primary ALL samples uncovered subtype-specific patterns of folate gene expression. Using an FPGS-luciferase reporter gene assay, we determined that E2A-PBX1 and TEL-AML1 expression decreased FPGS transcription. ChIP assays uncovered HDAC1, AML1, mSin3A, E2F, and Rb interactions with the FPGS promoter region. We demonstrate that FPGS expression is epigenetically regulated through binding of selected ALL fusions to a multiprotein complex, which also controls the cell cycle dependence of FPGS expression. This study provides insights into the pharmacogenomics of MTX in ALL subtypes.
Copyright © 2010 Elsevier Ltd. 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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Antimetabolites, Antineoplastic / pharmacokinetics
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Antimetabolites, Antineoplastic / therapeutic use
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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Cell Line
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Core Binding Factor Alpha 2 Subunit / genetics
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Core Binding Factor Alpha 2 Subunit / metabolism*
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Epigenesis, Genetic*
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Gene Expression Regulation, Enzymologic*
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Gene Expression Regulation, Leukemic*
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Histone Deacetylase 1 / genetics
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Histone Deacetylase 1 / metabolism
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Methotrexate / pharmacokinetics
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Methotrexate / therapeutic use
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Multiprotein Complexes / genetics
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Multiprotein Complexes / metabolism*
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism*
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Peptide Synthases / biosynthesis*
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Peptide Synthases / genetics
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Pre-B-Cell Leukemia Transcription Factor 1
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism*
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Promoter Regions, Genetic*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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Retinoblastoma Protein / genetics
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Retinoblastoma Protein / metabolism
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Transcription, Genetic*
Substances
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Antimetabolites, Antineoplastic
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Basic Helix-Loop-Helix Transcription Factors
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Core Binding Factor Alpha 2 Subunit
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DNA-Binding Proteins
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Multiprotein Complexes
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Oncogene Proteins, Fusion
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Pre-B-Cell Leukemia Transcription Factor 1
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Proto-Oncogene Proteins
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RUNX1 protein, human
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Retinoblastoma Protein
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TCF3 protein, human
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TEL-AML1 fusion protein
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PBX1 protein, human
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HDAC1 protein, human
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Histone Deacetylase 1
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Peptide Synthases
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folylpolyglutamate synthetase
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Methotrexate