The Isoform II of SRSF1: A Potential Biomarker in the Progression of Pediatric Acute Lymphoblastic Leukemia

Background: Acute lymphoblastic leukemia (ALL) is the most frequently occurring malignant neoplasm in children. Despite advances in treatment and outcomes for ALL patients, the pathogenesis of the disease remains unclear. Alternative splicing modulates the expression of many oncogene and tumor-suppressor isoforms. SRSF1, a prototypical SR protein has been recognized as an oncoprotein. SRSF1 has been reported to be auto-regulated into multiple isoforms that differ in function in various physiological or pathological conditions.

Methods: Matched, newly diagnosed (ND), complete remission (CR) and relapse (RE) bone marrow samples from 50 patients were collected in order to evaluate the expression patterns of SRSF1 spliced isoforms. The function of isoforms of SRSF1 in leukemogenesis was investigated in leukemia cell lines.

Results: Both in mRNA and protein level, we identified significant up-regulation of the three main spliced isoforms of SRSF1 and the isoform II is the main variant in the ND samples. Importantly, the expression of three isoforms of SRSF1 returned to normal levels after CR. But the protein isoforms rebound in the RE samples, and the isoform II is high expressed a short-term state prior to morphological or immunological change in the RE cases. We also observed the isoform II can promote significantly to the formation of cell clones.

Conclusion: Our results indicate that the alternative splicing of SRSF1 may plays a critical role in leukemogenesis in pediatric ALL, and the isoform II may be a sensitive predictor of relapse and a potential target for the anti-leukemic therapy.