title: GAS2-Calpain2 axis contributes to the growth of leukemic cells.
abstract: 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 silence prevented tumor formation of THP-1 cells in nude mice. In both THP-1 and Jurkat cells, GAS2 interacted with Calpain2 rather than Calpain1. The dominant negative form of GAS2 (GAS2DN, GAS2Δ171-313) 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 hematological malignancies and possibly to develop novel approaches to treat these deadly diseases.
authors.affiliation: Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Sun
authors.affiliation: Key Laboratory of Thrombosis and Hemostasis, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Suzhou 215006, China.
authors.forename: Haixia
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Thrombosis and Hemostasis, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Suzhou 215006, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Ge
authors.affiliation: Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, China.
authors.forename: Xiuyan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Ma
authors.affiliation: Key Laboratory of Thrombosis and Hemostasis, The First Affiliated Hospital of Soochow University, Jiangsu Institute of Hematology, Suzhou 215006, China Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215006, China zhaoy@suda.edu.cn wudepei@medmail.com.cn.
authors.forename: Depei
authors.initials: D
authors.lastname: Wu
authors.affiliation: Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, China Collaborative Innovation Center of Hematology, Soochow University, Suzhou 215006, China zhaoy@suda.edu.cn wudepei@medmail.com.cn.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D019169:Jurkat Cells; D007938:Leukemia / Q000378:metabolism* / Q000473:pathology*; D008840:Microfilament Proteins / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D014408:Biomarkers, Tumor; C490936:GAS2 protein, human; D008840:Microfilament Proteins; D002154:Calpain; C569870:CAPN2 protein, human
keywords: Calpain2; GAS2; GAS2DN; RNAi; immunoprecipitation