在无RAS激活突变的急性髓系白血病中检测处于活性GTP结合形式的N-RAS和K-RAS

Detection of N-RAS and K-RAS in their active GTP-bound form in acute myeloid leukemia without activating RAS mutations.

作者信息

Ehmann Falk, Horn Stefan, Garcia-Palma Lizet, Wegner Wiebke, Fiedler Walter, Giehl Klaudia, Mayr Georg W, Jücker Manfred

机构信息

Center of Experimental Medicine, Institute of Biochemistry and Molecular Biology I, Cellular Signal Transduction, University Hospital Hamburg-Eppendorf, Hamburg, Germany.

出版信息

Leuk Lymphoma. 2006 Jul;47(7):1387-91. doi: 10.1080/10428190600565925.

DOI:10.1080/10428190600565925

PMID:16923573

Abstract

RAS genes, predominantly N-RAS and K-RAS, have been implicated in the pathogenesis of acute myeloid leukemia (AML), due to activating RAS mutations detectable in approximately 20% of AML patients. In the present study, RAS proteins were detected in their activated, GTP-bound form, in AML patients (n = 10) not expressing mutated forms of H-RAS, K-RAS and N-RAS. Further analysis revealed the simultaneous presence of N-RAS and K-RAS proteins in the GTP-bound state in seven out of 10 AML samples. In four out of 10 samples the levels of RAS-GTP were comparable to an AML cell line (TF-1) with an activating N-RAS mutation (Q61P). The detection of RAS-GTP in AML patients without RAS mutations further supports a functional role of RAS proteins in the pathogenesis of AML and may explain the observed effects of RAS inhibitors in some AML patients in the absence of activating RAS mutations.

摘要

RAS基因，主要是N-RAS和K-RAS，已被认为与急性髓系白血病（AML）的发病机制有关，因为在大约20%的AML患者中可检测到激活的RAS突变。在本研究中，在不表达H-RAS、K-RAS和N-RAS突变形式的AML患者（n = 10）中，检测到处于激活的、GTP结合形式的RAS蛋白。进一步分析显示，在10个AML样本中的7个样本中同时存在处于GTP结合状态的N-RAS和K-RAS蛋白。在10个样本中的4个样本中，RAS-GTP的水平与具有激活型N-RAS突变（Q61P）的AML细胞系（TF-1）相当。在没有RAS突变的AML患者中检测到RAS-GTP，进一步支持了RAS蛋白在AML发病机制中的功能作用，并可能解释了在没有激活型RAS突变的情况下，RAS抑制剂在一些AML患者中所观察到的效果。