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Acute Leukemias

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

Leukemia volume 24, pages 552–562 (2010)Cite this article

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Abstract

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-γ-glutamate synthetase (FPGS) into long-chain polyglutamates (MTX-PG3−7), 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⩽0.8). SAHA increased the intracellular accumulation of long-chain MTX-PG3−7. Therefore, HDACI-induced FPGS expression increases the accumulation of MTX-PG3−7 and cytotoxicity in ALL cell lines, which is potentiated by DHFR and TS downregulation. The synergism exhibited by the combination of MTX and SAHA warrants clinical testing in ALL patients.

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Acknowledgements

We thank the Cancer Therapy Evaluation Program (CTEP), the National Cancer Institute, NIH.

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Authors and Affiliations

  1. Department of Pediatric Hematology and Oncology, University of Miami Miller School of Medicine, Miami, FL, USA

    G J Leclerc, G M Leclerc & J C Barredo

  2. UM Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA

    C Mou, A M Mian & J C Barredo

  3. Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA

    A M Mian

  4. Department of Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL, USA

    J C Barredo

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  1. G J Leclerc
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Correspondence to J C Barredo.

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This investigation was supported by the National Cancer Institute (NCI) (grant R01 CA098152, to JCB) and the Woman's Cancer Association of the University of Miami, Miami, FL, USA (to JCB and GJL).

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Leclerc, G., Mou, C., Leclerc, G. et al. Histone deacetylase inhibitors induce FPGS mRNA expression and intracellular accumulation of long-chain methotrexate polyglutamates in childhood acute lymphoblastic leukemia: implications for combination therapy. Leukemia 24, 552–562 (2010). https://doi.org/10.1038/leu.2009.282

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