Folylpolyglutamate synthetase gene transcription is regulated by a multiprotein complex that binds the TEL-AML1 fusion in acute lymphoblastic leukemia.
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.
Department of Pediatric Hematology and Oncology, University of Miami Miller School of Medicine, Miami, FL 33101, USA.
Guy J
GJ
Leclerc
Christopher
C
Sanderson
Stephen
S
Hunger
Meenakshi
M
Devidas
Julio C
JC
Barredo
D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics / Q000627:therapeutic use; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D044127:Epigenesis, Genetic; D015971:Gene Expression Regulation, Enzymologic; D015973:Gene Expression Regulation, Leukemic; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism; D008727:Methotrexate / Q000493:pharmacokinetics / Q000627:therapeutic use; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D010453:Peptide Synthases / Q000096:biosynthesis* / Q000235:genetics; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D000097764:ETS Translocation Variant 6 Protein
D000964:Antimetabolites, Antineoplastic; D051792:Basic Helix-Loop-Helix Proteins; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D056284:Histone Deacetylase 1; D008727:Methotrexate; D046912:Multiprotein Complexes; D015514:Oncogene Proteins, Fusion; D010453:Peptide Synthases; D000075062:Pre-B-Cell Leukemia Transcription Factor 1; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; C493728:RUNX1 protein, human; C407909:TCF3 protein, human; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein; C083400:PBX1 protein, human; C110550:HDAC1 protein, human; C023103:folylpolyglutamate synthetase