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-PG 37), 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-PG 37. Therefore, HDACI-induced FPGS expression increases the accumulation of MTX-PG 37 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.
| Original language | English |
|---|---|
| Pages (from-to) | 552-562 |
| Number of pages | 11 |
| Journal | Leukemia |
| Volume | 24 |
| Issue number | 3 |
| DOIs | |
| State | Published - Mar 1 2010 |
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Keywords
- ALL
- FPGS
- HDACI
- Methotrexate
- SAHA
ASJC Scopus subject areas
- Hematology
- Cancer Research
- Anesthesiology and Pain Medicine
Cite this
Histone deacetylase inhibitors induce FPGS mRNA expression and intracellular accumulation of long-chain methotrexate polyglutamates in childhood acute lymphoblastic leukemia : Implications for combination therapy. / Leclerc, G. J.; Mou, C.; Leclerc, G. M.; Mian, A. M.; Barredo, Julio.
In: Leukemia, Vol. 24, No. 3, 01.03.2010, p. 552-562.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Histone deacetylase inhibitors induce FPGS mRNA expression and intracellular accumulation of long-chain methotrexate polyglutamates in childhood acute lymphoblastic leukemia
T2 - Implications for combination therapy
AU - Leclerc, G. J.
AU - Mou, C.
AU - Leclerc, G. M.
AU - Mian, A. M.
AU - Barredo, Julio
PY - 2010/3/1
Y1 - 2010/3/1
N2 - 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-PG 37), 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-PG 37. Therefore, HDACI-induced FPGS expression increases the accumulation of MTX-PG 37 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.
AB - 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-PG 37), 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-PG 37. Therefore, HDACI-induced FPGS expression increases the accumulation of MTX-PG 37 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.
KW - ALL
KW - FPGS
KW - HDACI
KW - Methotrexate
KW - SAHA
UR - http://www.scopus.com/inward/record.url?scp=77949423718&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77949423718&partnerID=8YFLogxK
U2 - 10.1038/leu.2009.282
DO - 10.1038/leu.2009.282
M3 - Article
C2 - 20072153
AN - SCOPUS:77949423718
VL - 24
SP - 552
EP - 562
JO - Leukemia
JF - Leukemia
SN - 0887-6924
IS - 3
ER -