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

TY - JOUR

T1 - The association of aberrant folylpolyglutamate synthetase splicing with ex vivo methotrexate resistance and clinical outcome in childhood acute lymphoblastic leukemia

AU - Wojtuszkiewicz, Anna

AU - Assaraf, Yehuda G

AU - Hoekstra, Mirthe

AU - Sciarrillo, Rocco

AU - Jansen, Gerrit

AU - Peters, Godefridus J

AU - Pieters, Rob

AU - Sonneveld, Edwin

AU - Escherich, Gabriele

AU - Kaspers, Gertjan J L

AU - Cloos, Jacqueline

N1 - Document Type:Letter

PY - 2016/4/1

Y1 - 2016/4/1

N2 - 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.

AB - 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.

U2 - 10.3324/haematol.2016.142794

DO - 10.3324/haematol.2016.142794

M3 - Other (editorial matter etc.)

C2 - 27036162

VL - 101

SP - e291-4

JO - HAEMATOLOGICA

JF - HAEMATOLOGICA

SN - 0390-6078

IS - 7

ER -