BackgroundAcute lymphoblastic leukemia (ALL) is the most frequently-occurring malignant neoplasm in children, but the pathogenesis of the disease remains unclear. In a microarray assay using samples from 100 children with ALL, SFRS1 was found to be up-regulated. Serine/arginine-rich splicing factor 1 (SRSF1, also termed SF2/ASF), encoded by the SFRS1 gene, had been shown to be a pro-oncoprotein. Our previous study indicated that SRSF1 can be methylated by protein arginine methyltransferase 1 (PRMT1) in vitro; however, the biological function of SRSF1 and PRMT1 in pediatric ALL are presently unknown.MethodsMatched, newly diagnosed (ND), complete remission (CR) and relapse (RE) bone marrow samples from 57 patients were collected in order to evaluate the expression patterns of SRSF1 and PRMT1. The potential oncogenic mechanism of SRSF1 and PRMT1 in leukemogenesis was also investigated.ResultsWe identified significant up-regulation of SRSF1 and PRMT1 in the ND samples. Importantly, the expression of SRSF1 and PRMT1 returned to normal levels after CR, but rebounded in the RE samples. Our observation that SRSF1 could predict disease relapse was of particular interest, although the expression patterns of SRSF1 and PRMT1 were independent of the cytogenetic subtypes. In pre-B-cell lines, both SRSF1 and PRMT1 expression could be efficiently attenuated by the clinical chemotherapy agents arabinoside cytosine (Ara-c) or vincristine (VCR). Moreover, SRSF1 and PRMT1 were associated with each other in leukemia cells in vivo. Knock-down of SRSF1 resulted in an increase in early apoptosis, which could be further induced by chemotherapeutics.ConclusionsOur results indicate that SRSF1 serves as an anti-apoptotic factor and potentially contributes to leukemogenesis in pediatric ALL patients by cooperating with PRMT1.
Serine/arginine‐rich splicing factor 1 (SRSF1) has been linked to various human cancers including pediatric acute lymphoblastic leukemia (ALL). Our previous study has shown that SRSF1 potentially contributes to leukemogenesis; however, its underlying mechanism remains unclear. In this study, leukemic cells were isolated from pediatric ALL bone marrow samples, followed by immunoprecipitation assays and mass spectrometry analysis specific to SRSF1. Subcellular localization of the SRSF1 protein and its mutants were analyzed by immunofluorescence staining. Cell growth, colony formation, cell apoptosis, and the cell cycle were investigated using stable leukemic cell lines generated with lentivirus‐mediated overexpressed WT or mutant plasmids. Cytotoxicity of the Tie2 kinase inhibitor was also evaluated. Our results showed the phosphorylation of SRSF1 at tyrosine 19 (Tyr‐19) was identified in newly diagnosed ALL samples, but not in complete remission or normal control samples. Compared to the SRSF1 WT cells, the missense mutants of the Tyr‐19 phosphorylation affected the subcellular localization of SRSF1. In addition, the Tyr‐19 phosphorylation of SRSF1 also led to increased cell proliferation and enhanced colony‐forming properties by promoting the cell cycle. Remarkably, we further identified the kinase Tie2 as a potential therapeutic target in leukemia cells. In conclusion, we identify for the first time that the phosphorylation state of SRSF1 is linked to different phases in pediatric ALL. The Tyr‐19 phosphorylation of SRSF1 disrupts its subcellular localization and promotes proliferation in leukemia cells by driving cell‐cycle progression. Inhibitors targeting Tie2 kinase that could catalyze Tyr‐19 phosphorylation of SRSF1 offer a promising therapeutic target for treatment of pediatric ALL.
4298 Acute lymphoblastic leukemia (ALL) is the most frequent-occurring malignant neoplasm in children, but the pathogenesis of the disease remains unclear. In a microarray assay using samples from 100 Chinese children with ALL, CTCF was found to be up-regulated. DNA-binding nuclear protein CTCF (encoded by CTCF gene) is a highly conserved zinc finger protein involved in multiple cellular processes including transcriptional activation/repression, insulation, imprinting and × chromosome inactivation. It has been shown to be associated with cell apoptosis and differentiation in tumors; however, the biological function of CTCF in pediatric ALL is presently unknown. To investigate the expression features of CTCF in pediatric ALL cells, matched newly diagnosis (ND), complete remission (CR) and relapse (RE) bone marrow samples from 24 patients were collected. Ten ND-CR paired samples (n=20) were selected to detect the mRNA levels of CTCF by Q-PCR. Besides, the protein levels of CTCF at different stages of disease progression were measured by western blot in all patients (20 ND-CR paired samples, n=40; 4 ND-CR-RE matched samples, n=12). To further explore the role of CTCF in the pathogenesis of leukemia, the potential effect of CTCF on the cell apoptosis in lymphoblastic cells was investigated by flow cytometry. We identified significant up-regulation of CTCF in the ND samples. Importantly, the expression of CTCF returned to normal level after CR, but rebounded in the RE samples. Knock-down of CTCF resulted in nearly 3–fold and 15–fold increases in early and late apoptosis of leukemic cells respectively, which indicated that CTCF is an anti-apoptotic factor and plays an anti-apoptotic role in lymphoblastic cells. Our results indicate that CTCF may represent a promising indicator of disease progression as well as reflecting the ongoing therapeutic effects of treatment. Furthermore, CTCF serves as an anti-apoptotic factor and potentially contributes to leukemogenesis in pediatric ALL patients. Disclosures: Zhang: Beijing Health System High-level Technical Personel Plan: Research Funding. Zheng:Beijing Health System High-level Technical Personel Plan: Research Funding.
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