Folylpolyglutamate synthetase splicing alterations in acute lymphoblastic leukemia are provoked by methotrexate and other chemotherapeutics and mediate chemoresistance

Anna Wojtuszkiewicz, Shachar Raz, Michal Stark, Yehuda G. Assaraf, Gerrit Jansen, Godefridus J. Peters, Edwin Sonneveld, Gertjan J.L. Kaspers, Jacqueline Cloos

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

35 Citaten (Scopus)

Samenvatting

Methotrexate (MTX), a folate antagonist which blocks de novo nucleotide biosynthesis and DNA replication, is an anchor drug in acute lymphoblastic leukemia (ALL) treatment. However, drug resistance is a primary hindrance to curative chemotherapy in leukemia and its molecular mechanisms remain poorly understood. We have recently shown that impaired folylpolyglutamate synthetase (FPGS) splicing possibly contributes to the loss of FPGS activity in MTX-resistant leukemia cell line models and adult leukemia patients. However, no information is available on the possible splicing alterations in FPGS in pediatric ALL. Here, using a comprehensive PCR-based screen we discovered and characterized a spectrum of FPGS splicing alterations including exon skipping and intron retention, all of which proved to frequently emerge in both pediatric and adult leukemia patient specimens. Furthermore, an FPGS activity assay revealed that these splicing alterations resulted in loss of FPGS function. Strikingly, pulse-exposure of leukemia cells to antifolates and other chemotherapeutics markedly enhanced the prevalence of several FPGS splicing alterations in antifolate-resistant cells, but not in their parental antifolate-sensitive counterparts. These novel findings suggest that an assortment of deleterious FPGS splicing alterations may constitute a mechanism of antifolate resistance in childhood ALL. Our findings have important implications for the rational overcoming of drug resistance in individual leukemia patients.

Originele taal-2Engels
Pagina's (van-tot)1645-1656
Aantal pagina's12
TijdschriftInternational Journal of Cancer
Volume138
Nummer van het tijdschrift7
DOI's
StatusGepubliceerd - 1 apr. 2016
Extern gepubliceerdJa

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