期刊
HAEMATOLOGICA
卷 105, 期 9, 页码 2316-2326出版社
FERRATA STORTI FOUNDATION
DOI: 10.3324/haematol.2019.223024
关键词
-
类别
资金
- Deutsche Forschungsgemeinschaft [KFO 216]
- Interdisziplinares Zentrum fur Klinische Forschung of the Universitatsklinikum Wurzburg [B-188]
- Else Kroner Fresenius-Stiftung [2010_Kolleg.52]
- Deutsche Krebshilfe [70112693]
Oncogenic RAS provides crucial survival signaling for up to half of multiple myeloma (MM) cases, but has so far remained a clinically undruggable target. RAS-like protein (RAL) is a member of the RAS superfamily of small GTPases and is considered to be a potential mediator of oncogenic RAS signaling. In primary MM, we found RAL to be overex-pressed in the vast majority of samples when compared with pre-malignant monoclonal gammopathy of undetermined significance or normal plasma cells. We analyzed the functional effects of RAL abrogation in myeloma cell lines and found that RAL is a critical mediator of survival. RNAi-mediated knockdown of RAL resulted in rapid induction of tumor cell death, an effect which was independent from signaling via mitogen-activated protein kinase, but appears to be partially dependent on Akt activity. Notably, RAL activation was not correlated with the presence of activating RAS muta-tions and remained unaffected by knockdown of oncogenic RAS. Furthermore, transcriptome analysis yielded distinct RNA expression signa-tures after knockdown of either RAS or RAL. Combining RAL depletion with clinically relevant anti-myeloma agents led to enhanced rates of cell death. Our data demonstrate that RAL promotes MM cell survival inde-pendently of oncogenic RAS and, thus, this pathway represents a potential therapeutic target in its own right.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据