Folylpolyglutamate Synthetase Gene Transcription is Regulated by a Multiprotein Complex that Binds the TEL-AML1 Fusion in Acute Lymphoblastic Leukemia

Guy Jacques Leclerc, Christopher Sanderson, Stephen Hunger, Meenakshi Devidas, Julio C. Barredo

Research output: Contribution to journalArticle

12 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1601-1609
Number of pages9
JournalLeukemia Research
Volume34
Issue number12
DOIs
StatePublished - Dec 1 2010

Keywords

  • ALL
  • Chromatin remodeling
  • FPGS
  • HDAC1
  • Leukemia
  • Methotrexate
  • Rb/E2F
  • TEL-AML1

ASJC Scopus subject areas

  • Cancer Research
  • Hematology
  • Oncology

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