Histone deacetylase inhibitors induce FPGS mRNA expression and intracellular accumulation of long-chain methotrexate polyglutamates in childhood acute lymphoblastic leukemia: implications for combination therapy.

Children with acute lymphoblastic leukemia (ALL) diagnosed with resistant phenotypes, and those who relapse, have a dismal prognosis for cure. The antifolate methotrexate (MTX), a universal component of ALL therapies, is metabolized by folylpoly-gamma-glutamate synthetase (FPGS) into long-chain polyglutamates (MTX-PG(3-7)), resulting in enhanced cytotoxicity from prolonged inhibition of dihydrofolate reductase ...
(DHFR) and thymidylate synthetase (TS). Using DNaseI assays, we identified a hypersensitive site upstream from exon-1, suggesting chromatin remodeling could alter FPGS expression. We demonstrated that histone deacetylase-1 (HDAC1) is recruited by NFY and Sp1 transcription factors to the FPGS promoter in ALL cell lines. We examined the effect of histone deacetylase inhibitors (HDACIs) sodium butyrate and suberoylanilide hydroxamic acid (SAHA) on the expression of FPGS and other folate-related genes. HDACIs increased FPGS mRNA expression by 2- to 5-fold, whereas DHFR and TS mRNA expression was decreased. Combination treatment with MTX plus SAHA significantly increased cytotoxicity and apoptosis in B- and T-ALL cell lines as compared with each drug alone (CI
Mesh Terms:
Antineoplastic Combined Chemotherapy Protocols, CCAAT-Binding Factor, Cell Line, Tumor, Exons, Gene Expression Regulation, Enzymologic, Histone Deacetylase 1, Histone Deacetylase Inhibitors, Humans, Hydroxamic Acids, Methotrexate, Peptide Synthases, Polyglutamic Acid, Precursor Cell Lymphoblastic Leukemia-Lymphoma, Sp1 Transcription Factor
Leukemia
Date: Mar. 01, 2010
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