The association of aberrant folylpolyglutamate synthetase splicing with ex vivo methotrexate resistance and clinical outcome in childhood acute lymphoblastic leukemia

  • Anna Wojtuszkiewicz
  • Yehuda G Assaraf
  • Mirthe Hoekstra
  • Rocco Sciarrillo
  • Gerrit Jansen
  • Godefridus J Peters
  • Rob Pieters
  • Edwin Sonneveld
  • Gabriele Escherich
  • Gertjan J L Kaspers
  • Jacqueline Cloos

Abstract

The antifolate methotrexate (MTX) is one of the pillars of acute lymphoblastic leukemia (ALL) treatment. However, the efficacy of MTX is frequently hampered by drug resistance, which can contribute to relapse. Although a multitude of molecular mechanisms underlie drug resistance in model cell lines, their clinical relevance often remains elusive. The activity of folylpolyglutamate synthetase (FPGS) enzyme is essential for intracellular retention and cytotoxic activity of MTX. Hence, alterations in the FPGS gene are a plausible contributor to impaired FPGS activity in MTX-resistant leukemia cells. Here we studied the association of FPGS splicing alterations with ex vivo MTX resistance as well as clinical response in 91 pediatric ALL patients. Our findings reveal that one FPGS splicing alteration- intron 8 partial retention (8 PR) exhibited a significant association with overall survival (HR=5.55, P=0.003) and event-free survival (HR=4.24, P=0.024) in a subset of patients displaying impaired accumulation of long-chain MTX polyglutamates. Moreover, high levels of intron 8 PR were indicative of resistance to several other chemotherapeutics including glucocorticoids, suggesting that the presence of intron 8 PR reflects a broader splicing defect resulting in multidrug resistance. These findings have important implications for personalized treatment and the circumvention of drug resistance in ALL patients.

Bibliographical data

Original languageEnglish
ISSN0390-6078
DOIs
Publication statusPublished - 01.04.2016

Comment Deanary

Document Type:Letter

PubMed 27036162