GAS2-Calpain2 axis contributes to the growth of leukemic cells  

作　　者：LUi Sun Haixia Zhou Hong Liu Yue Ge Xiuyan Zhang Wenjuan Ma Depei Wu Yun Zhao 

机构地区：[1]Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, China [2]Key Laboratory of Thrombosis and Hemostasis, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Suzhou 215006, China [3]Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215006, China

出　　处：《Acta Biochimica et Biophysica Sinica》2015年第10期795-804,共10页生物化学与生物物理学报（英文版）

基　　金：These authors are grateful to the generous gift of spermine-introduced pullulan as a robust carrier for siRNA delivery from Drs Jian Liu and Haiyan Xu （Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences ＆ Peking Union Medical College, Beijing, China）.This work was supported by the grants from the National Natural Science Foundation of China （Nos. 31371392 and 81400113）, the National Key Scientific Project of China （No. 2011CB933501）, the Priority Academic Program Development of Jiangsu Higher Education Institutions （PAPD）, Jiangsu Province＇s Key Medical Center （ZX201102）, and National Public Health Grand Research Foundation （No. 201202017）.

摘　　要：Growth arrest specific 2 （GAS2） modulates cell cycle, apoptosis, and Calpain activity. GAS2-Calpain2 axis is required for the growth of BCR-ABL＋ hematopoietic cells and chronic myeloid leukemia cells. However, the expression of GAS2 in acute leukemia patients remains unclear and what role GAS2- Calpain2 axis plays in these leukemic cells is not known yet. In this study, GAS2 was found to have significantly higher expression in 16 various leukemic cell lines than in control cells. Using THP-1 cells （from acute myeloid leukemia patient, AML） and Jurkat cells （from acute lymphoid leukemia patient, ALL） as models, we found that GAS2 silence led to elevated Calpain activity, decreased cellular growth, and inhibition of colony-forming cell （CFC） production; and these effects could be rescued by GAS2 re-expression. Moreover, GAS2 s nude mice. In both THP-1 and Jurkat cells, GAS2 ence prevented tumor formation of THP-1 cells in nteracted with Calpain2 rather than Calpainl. The dominant negative form of GAS2 （GAS2DN, GAS2A171-313） had similar effects on leukemic cells through the activation of Calpain. Importantly, Calpain2 silence abolished the proliferation inhibition induced by GAS2 targeting. We also found that GAS2 was aberrantly expressed and Calpain activity was decreased in clinical isolates from acute leukemia patients. Taken together, our results demonstrated the deregulation of GAS2 in both AML and ALL and the requirement of GAS2-Calpain2 axis for the growth of leukemic cells, which will help to understand the molecular pathogenesis of hema- tological malignancies and possibly to develop novel approaches to treat these deadly diseases.Growth arrest specific 2 （GAS2） modulates cell cycle, apoptosis, and Calpain activity. GAS2-Calpain2 axis is required for the growth of BCR-ABL＋ hematopoietic cells and chronic myeloid leukemia cells. However, the expression of GAS2 in acute leukemia patients remains unclear and what role GAS2- Calpain2 axis plays in these leukemic cells is not known yet. In this study, GAS2 was found to have significantly higher expression in 16 various leukemic cell lines than in control cells. Using THP-1 cells （from acute myeloid leukemia patient, AML） and Jurkat cells （from acute lymphoid leukemia patient, ALL） as models, we found that GAS2 silence led to elevated Calpain activity, decreased cellular growth, and inhibition of colony-forming cell （CFC） production; and these effects could be rescued by GAS2 re-expression. Moreover, GAS2 s nude mice. In both THP-1 and Jurkat cells, GAS2 ence prevented tumor formation of THP-1 cells in nteracted with Calpain2 rather than Calpainl. The dominant negative form of GAS2 （GAS2DN, GAS2A171-313） had similar effects on leukemic cells through the activation of Calpain. Importantly, Calpain2 silence abolished the proliferation inhibition induced by GAS2 targeting. We also found that GAS2 was aberrantly expressed and Calpain activity was decreased in clinical isolates from acute leukemia patients. Taken together, our results demonstrated the deregulation of GAS2 in both AML and ALL and the requirement of GAS2-Calpain2 axis for the growth of leukemic cells, which will help to understand the molecular pathogenesis of hema- tological malignancies and possibly to develop novel approaches to treat these deadly diseases.

关 键 词：GAS2 Calpain2 RNAI GAS2DN IMMUNOPRECIPITATION 

分 类 号：Q943.1[生物学—植物学] O614.33[理学—无机化学]