RalA, a GTPase targeted by miR-181a, promotes transformation and progression by activating the Ras-related signaling pathway in chronic myelogenous leukemia.

// Chunming Gu 1, 2, * , Maoxiao Feng 1, * , Zhao Yin 1, * , Xiaochuang Luo 1 , Juhua Yang 1 , Yumin Li 1 , Tianfu Li 3 , Ruirui Wang 3 , Jia Fei 1, 2 1 Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou 510632, China 2 Insititute of Chinese Integrative Medicine, Medical College of Jinan University, Guangzhou 510632, China 3 Department of Clinical Medicine, Medical College of Jinan University, Guangzhou 510632, China * These authors have contributed equally to this work Correspondence to: Jia Fei, e-mail: efeijia@163.com Keywords: RalA GTPases, chronic myelogenous leukemia, malignant transformation, imatinib, Ras signaling pathway Received: September 04, 2015      Accepted: February 16, 2016      Published: March 08, 2016 ABSTRACT BCR/ABL is a well-known activator of multiple signaling pathways. RalA, a Ras downstream signaling molecule and a small GTPase, plays an important role in Bcr-Abl-induced leukemogenesis but the exact mechanism remains elusive. Here, we show that RalA GTPase activity is commonly high in chronic myelogenous leukemia (CML) cell lines and patient samples. Overexpression of RalA results in malignant transformation and progression, and induces resistance to imatinib (IM) in BaF3 and K562 cell lines. RalA reduced survival and led to IM resistance in a xenografted mouse model. Ablation of RalA by either siRNA or miR-181a, a RalA targeting microRNA, attenuated the malignant phenotypes in K562 cells. RBC8, a selective Ral inhibitor, enhanced the inhibitory effects of IM in K562, KCL22 and BaF3-P210 cells. Interestingly, the phospho-specific protein microarray assay revealed that multiple phosphorylation signal proteins were decreased by RalA inhibition, including SAPK, JNK, SRC, VEGFR2, P38 MAPK, c-Kit, JunB, and Keratin18. Among them, P38 MAPK and SAPK/JNK are Ras downstream signaling kinases. Taken together, RalA GTPase might be an important oncogene activating the Ras-related signaling pathway in CML.