Reduced folate carrier and dihydrofolate reductase expression in acute lymphocytic leukemia may predict outcome: A Children's Cancer Group study

Adam S. Levy, Harland N. Sather, Peter G. Steinherz, Rebecca Sowers, Mei La, Jeffrey A. Moscow, Paul S. Gaynon, Fatih M. Uckun, Joseph R. Bertino, Richard Gorlick

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Purpose: Methotrexate is a major component of current treatment regimens for children with acute lymphocytic leukemia (ALL). Potential mechanisms of methotrexate resistance include impaired drug uptake, decreased drug retention, and dihydrofolate reductase (DHFR) amplification. The purpose of this study was to assess whether reduced folate carrier (RFC) and DHFR expression in untreated leukemic blasts correlated with outcome. Methods: Quantitative real-time RT-PCR was used to measure RFC and DHFR mRNA expression in leukemic blasts from 40 newly diagnosed patients with ALL obtained in a blinded fashion from Children's Cancer Group studies. Results: Low RFC expression at diagnosis correlated significantly with an unfavorable event free survival. Surprisingly, low, not high, DHFR expression correlated significantly with an unfavorable event-free survival. Proliferative cell nuclear antigen (PCNA) expression demonstrated a weak inverse relationship between sample PCNA and DHFR or RFC expression, suggesting that DHFR and RFC expression may be markers for factors other than drug resistance. Conclusions: These results suggest that impaired transport may be an important mechanism of intrinsic methotrexate resistance in ALL, and DHFR expression also may be an important prognostic factor in ALL. Additional studies are necessary to clarify the mechanism for the correlation of low DHFR expression with poor outcome.

Original languageEnglish (US)
Pages (from-to)688-695
Number of pages8
JournalJournal of Pediatric Hematology/Oncology
Volume25
Issue number9
DOIs
StatePublished - Sep 1 2003
Externally publishedYes

Fingerprint

Reduced Folate Carrier Protein
Tetrahydrofolate Dehydrogenase
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Neoplasms
Methotrexate
Nuclear Antigens
Disease-Free Survival
Drug Resistance
Pharmaceutical Preparations
Real-Time Polymerase Chain Reaction

Keywords

  • Drug resistance
  • Methotrexate
  • Quantitative real-time RT-PCR

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Oncology
  • Hematology

Cite this

Reduced folate carrier and dihydrofolate reductase expression in acute lymphocytic leukemia may predict outcome : A Children's Cancer Group study. / Levy, Adam S.; Sather, Harland N.; Steinherz, Peter G.; Sowers, Rebecca; La, Mei; Moscow, Jeffrey A.; Gaynon, Paul S.; Uckun, Fatih M.; Bertino, Joseph R.; Gorlick, Richard.

In: Journal of Pediatric Hematology/Oncology, Vol. 25, No. 9, 01.09.2003, p. 688-695.

Research output: Contribution to journalArticle

Levy, Adam S. ; Sather, Harland N. ; Steinherz, Peter G. ; Sowers, Rebecca ; La, Mei ; Moscow, Jeffrey A. ; Gaynon, Paul S. ; Uckun, Fatih M. ; Bertino, Joseph R. ; Gorlick, Richard. / Reduced folate carrier and dihydrofolate reductase expression in acute lymphocytic leukemia may predict outcome : A Children's Cancer Group study. In: Journal of Pediatric Hematology/Oncology. 2003 ; Vol. 25, No. 9. pp. 688-695.
@article{aca43f2c39d44f26bd4f19bc072386ca,
title = "Reduced folate carrier and dihydrofolate reductase expression in acute lymphocytic leukemia may predict outcome: A Children's Cancer Group study",
abstract = "Purpose: Methotrexate is a major component of current treatment regimens for children with acute lymphocytic leukemia (ALL). Potential mechanisms of methotrexate resistance include impaired drug uptake, decreased drug retention, and dihydrofolate reductase (DHFR) amplification. The purpose of this study was to assess whether reduced folate carrier (RFC) and DHFR expression in untreated leukemic blasts correlated with outcome. Methods: Quantitative real-time RT-PCR was used to measure RFC and DHFR mRNA expression in leukemic blasts from 40 newly diagnosed patients with ALL obtained in a blinded fashion from Children's Cancer Group studies. Results: Low RFC expression at diagnosis correlated significantly with an unfavorable event free survival. Surprisingly, low, not high, DHFR expression correlated significantly with an unfavorable event-free survival. Proliferative cell nuclear antigen (PCNA) expression demonstrated a weak inverse relationship between sample PCNA and DHFR or RFC expression, suggesting that DHFR and RFC expression may be markers for factors other than drug resistance. Conclusions: These results suggest that impaired transport may be an important mechanism of intrinsic methotrexate resistance in ALL, and DHFR expression also may be an important prognostic factor in ALL. Additional studies are necessary to clarify the mechanism for the correlation of low DHFR expression with poor outcome.",
keywords = "Drug resistance, Methotrexate, Quantitative real-time RT-PCR",
author = "Levy, {Adam S.} and Sather, {Harland N.} and Steinherz, {Peter G.} and Rebecca Sowers and Mei La and Moscow, {Jeffrey A.} and Gaynon, {Paul S.} and Uckun, {Fatih M.} and Bertino, {Joseph R.} and Richard Gorlick",
year = "2003",
month = "9",
day = "1",
doi = "10.1097/00043426-200309000-00004",
language = "English (US)",
volume = "25",
pages = "688--695",
journal = "Journal of Pediatric Hematology/Oncology",
issn = "1077-4114",
publisher = "Lippincott Williams and Wilkins",
number = "9",

}

TY - JOUR

T1 - Reduced folate carrier and dihydrofolate reductase expression in acute lymphocytic leukemia may predict outcome

T2 - A Children's Cancer Group study

AU - Levy, Adam S.

AU - Sather, Harland N.

AU - Steinherz, Peter G.

AU - Sowers, Rebecca

AU - La, Mei

AU - Moscow, Jeffrey A.

AU - Gaynon, Paul S.

AU - Uckun, Fatih M.

AU - Bertino, Joseph R.

AU - Gorlick, Richard

PY - 2003/9/1

Y1 - 2003/9/1

N2 - Purpose: Methotrexate is a major component of current treatment regimens for children with acute lymphocytic leukemia (ALL). Potential mechanisms of methotrexate resistance include impaired drug uptake, decreased drug retention, and dihydrofolate reductase (DHFR) amplification. The purpose of this study was to assess whether reduced folate carrier (RFC) and DHFR expression in untreated leukemic blasts correlated with outcome. Methods: Quantitative real-time RT-PCR was used to measure RFC and DHFR mRNA expression in leukemic blasts from 40 newly diagnosed patients with ALL obtained in a blinded fashion from Children's Cancer Group studies. Results: Low RFC expression at diagnosis correlated significantly with an unfavorable event free survival. Surprisingly, low, not high, DHFR expression correlated significantly with an unfavorable event-free survival. Proliferative cell nuclear antigen (PCNA) expression demonstrated a weak inverse relationship between sample PCNA and DHFR or RFC expression, suggesting that DHFR and RFC expression may be markers for factors other than drug resistance. Conclusions: These results suggest that impaired transport may be an important mechanism of intrinsic methotrexate resistance in ALL, and DHFR expression also may be an important prognostic factor in ALL. Additional studies are necessary to clarify the mechanism for the correlation of low DHFR expression with poor outcome.

AB - Purpose: Methotrexate is a major component of current treatment regimens for children with acute lymphocytic leukemia (ALL). Potential mechanisms of methotrexate resistance include impaired drug uptake, decreased drug retention, and dihydrofolate reductase (DHFR) amplification. The purpose of this study was to assess whether reduced folate carrier (RFC) and DHFR expression in untreated leukemic blasts correlated with outcome. Methods: Quantitative real-time RT-PCR was used to measure RFC and DHFR mRNA expression in leukemic blasts from 40 newly diagnosed patients with ALL obtained in a blinded fashion from Children's Cancer Group studies. Results: Low RFC expression at diagnosis correlated significantly with an unfavorable event free survival. Surprisingly, low, not high, DHFR expression correlated significantly with an unfavorable event-free survival. Proliferative cell nuclear antigen (PCNA) expression demonstrated a weak inverse relationship between sample PCNA and DHFR or RFC expression, suggesting that DHFR and RFC expression may be markers for factors other than drug resistance. Conclusions: These results suggest that impaired transport may be an important mechanism of intrinsic methotrexate resistance in ALL, and DHFR expression also may be an important prognostic factor in ALL. Additional studies are necessary to clarify the mechanism for the correlation of low DHFR expression with poor outcome.

KW - Drug resistance

KW - Methotrexate

KW - Quantitative real-time RT-PCR

UR - http://www.scopus.com/inward/record.url?scp=0042735078&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0042735078&partnerID=8YFLogxK

U2 - 10.1097/00043426-200309000-00004

DO - 10.1097/00043426-200309000-00004

M3 - Article

C2 - 12972803

AN - SCOPUS:0042735078

VL - 25

SP - 688

EP - 695

JO - Journal of Pediatric Hematology/Oncology

JF - Journal of Pediatric Hematology/Oncology

SN - 1077-4114

IS - 9

ER -