Involvement of SRSF1 in Alternative Splicing of FPGS and Methotrexate Resistance in Children with Acute Lymphoblastic Leukemia
AbstractMethotrexate (MTX) is a key component in treatment of childhood ALL. Impaired polyglutamation is a known mechanism of MTX-resistance. To date, a spectrum of splicing alterations was identified for folypoly-γ-glutamate synthetase (FPGS), the enzyme which catalyzes polyglutamation. The serine/arginine-rich splicing factor 1 (SRSF1) is involved in both constitutive and alternative splicing. We found an association between the expression of SRSF1 isoforms, ASF1 and ASF3, and alternative splice variants of FPGS. Moreover, in a subgroup of patients with deficient polyglutamation, the ratio of ASF3 to ASF1 was associated with survival. Therefore splice regulators are potential prognostic markers for both patient stratification and personalized medicine in childhood ALL.
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