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Cancer Science Volume 109 ,Issue 12 ,2018-11-14
Phosphorylation of serine/arginine‐rich splicing factor 1 at tyrosine 19 promotes cell proliferation in pediatric acute lymphoblastic leukemia
Liting Xu 1 Han Zhang 1 Mei Mei 2 Chaohao Du 2 Xiahe Huang 2 Jing Li 1 Yingchun Wang 2 Shilai Bao 2 Huyong Zheng 1
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Received 2018-05-01, accepted for publication 2018-10-04, Published 2018-10-04

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.


tyrosine phosphorylation;Tie2 kinase;SRSF;childhood;acute lymphoblastic leukemia


© 2018 Japanese Cancer Association
This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.


1. Shilai Bao.Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.slbao@genetics.ac.cn
2. Huyong Zheng.Beijing Key Laboratory of Pediatric Hematology Oncology, National Key Discipline of Pediatrics, Ministry of Education, Key Laboratory of Major Diseases in Children, Ministry of Education, Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children’s Health, Beijing, China.slbao@genetics.ac.cn


Liting Xu,Han Zhang,Mei Mei,Chaohao Du,Xiahe Huang,Jing Li,Yingchun Wang,Shilai Bao,Huyong Zheng. Phosphorylation of serine/arginine‐rich splicing factor 1 at tyrosine 19 promotes cell proliferation in pediatric acute lymphoblastic leukemia. Cancer Science ,Vol.109, Issue 12(2018)



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