Involvement of SRSF1 in Alternative Splicing of FPGS and Methotrexate Resistance in Children with Acute Lymphoblastic Leukemia


  • Inge van der Werf VU Medical Center
  • Jacqueline Cloos VU Medical Center


Methotrexate (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.

Author Biographies

Inge van der Werf, VU Medical Center

Dept. of Pediatric Oncology/Hematology Cancer Center Amsterdam, VUMC

Jacqueline Cloos, VU Medical Center

Dept. of Pediatric Oncology/Hematology Cancer Center Amsterdam, VUMC


Pui et al. (2012). Pediatric acute lymphoblastic leukemia: where are we going and how do we get there? Blood. 120:1165-1174

Assaraf, Y.G. (2007). Molecular basis of antifolate resistance. Cancer Metastasis Rev. 26:153-181

Rots et al. (1999). Leukemia in Methotrexate Accumulation and Polyglutamylation in Childhood Role of Folylpolyglutamate Synthetase and Folylpolyglutamate Hydrolase. Blood Journal. 93: 1677-1683

Stark et al. (2009). Aberrant splicing of folylpolyglutamate synthetase as a novel mechanism of

antifolate resistance in leukemia. Lymphoid Neoplasia. 113: 4362-4369

Unpublished data, Anna Wojtuszkiewicz et al.

Krainer et al. (2014). Emerging functions of SRSF1, splicing factor and oncoprotein, in RNA metabolism and cancer. Molecular Cancer research.

Zhu et al. (2000). Pre-mRNA splicing in the absence of an SR protein RS domain. Genes and development. 14:3166-3178

Zuo et al. (1993). Funtional domains of the human splicing factor ASF/SF2. The EMBO Journal. 12(12):4727-4737

Shaw et al. (2007) Deletion of the N-terminus of SF2/ASF permits RS-domain-independent pre-mRNA splicing. PLoS One. 2:e854

Franke et al. (2012). Impaired bortezomib binding to mutant β5 subunit of the proteasome is the underlying basis for bortezomib resistance in leukemia cells. Leukemia. 26, 757–768

Desmet et al. (2009). Human Splicing Finder. Nucleic Acid Research. 37(9):e67.






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