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.
Highlights
Chronic myelogenous leukemia (CML) is a malignant disorder of hematopoietic stem cells that arises from reciprocal translocation between the BCR gene on chromosome 22 and the ABL gene on chromosome 9, t (9;22) (q34;q11), called Philadelphia chromosome [1, 2]
Increased RalA GTPase activity increases malignant transformation in CML cells We have previously shown that miR‐181a directly targets RalA GTPase in CML cells [18, 19]
RalA GTPase activity was significantly decreased upon inhibition of RalA expression with either overexpression of miR‐181a mimic or RalA siRNA (Figure 1B)
Summary
Chronic myelogenous leukemia (CML) is a malignant disorder of hematopoietic stem cells that arises from reciprocal translocation between the BCR gene on chromosome 22 and the ABL gene on chromosome 9, t (9;22) (q34;q11), called Philadelphia chromosome [1, 2]. The enhanced tyrosine kinase (TK) activity of BCR/ABL plays a critical role in hematopoietic cell transformation in CML. Imatinib mesylate (IM), a small molecule tyrosine kinase inhibitor (TKI) that binds to the ATP‐binding site of ABL and inhibits BCR‐ABL kinase activity, has proven to be a revolutionary treatment for patients with CML [3,4,5]. In ~20% of CML cases, TKI resistance is not caused by altered BCR/ABL function. This BCR/ ABL‐independent IM resistance is not well understood [7, 8]. The Ras pathway is activated by BCR/ABL and plays a key role in BCR/ABL‐controlled leukemogenesis [9, 10]. Inhibiting the Ras signaling pathway might be a prospective strategy for overcoming IM resistance in CML
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