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RalA, a GTPase Targeted by miR-181a, Promotes Transformation and Progression by Activating the Ras-related Signaling Pathway in Chronic Myelogenous Leukemia

RalA, a GTPase Targeted by miR-181a, Promotes Transformation and Progression by Activating the Ras-related Signaling Pathway in Chronic Myelogenous Leukemia

Chunming Gu, Maoxiao Feng, Zhao Yin, Xiaochuang Luo, Juhua Yang, Yumin Li, Tianfu Li, Ruirui Wang, Jia Fei

Oncotarget. 2016 Apr 12;7(15):20561-73.

PMID: 26967392

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP361185424	RBC8		361185-42-4	Price

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