Enhanced MAPK signaling is essential for CSF3R-induced leukemia.
Enhanced MAPK signaling is essential for CSF3R-induced leukemia.
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DOI：
10.1038/leu.2016.376
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发表时间：
2017-08
期刊：
影响因子：
11.4
通讯作者：
Azam M
中科院分区：
文献类型：
--
作者：
Rohrabaugh S;Kesarwani M;Kincaid Z;Huber E;Leddonne J;Siddiqui Z;Khalifa Y;Komurov K;Grimes HL;Azam M
CSF 3R的近膜突变和截短突变最近被报道可导致慢性嗜中性粒细胞白血病（CNL）的发生。在这里，我们表明，虽然截断突变单独不能诱导白血病，近端和复合突变（近端和截断突变相同的等位基因）是白血病的疾病潜伏期分别为90和23天。比较全基因组表达谱和生化实验表明，诱导表达的Mapk衔接蛋白Ksr 1和增强的Mapk信号传导是至关重要的白血病由CSF 3R近端和复合突变体。此外，曲美替尼单独抑制Mek 1/2足以抑制由CSF 3R近端和鲁索利替尼耐药化合物突变诱导的白血病。总之，这些发现阐明了CSF 3R诱导的发病机制的Mapk依赖性机制，并且它们建立了CNL中MEK 1/2抑制的临床评价的基本原理。
Both membrane-proximal and truncation mutations in CSF3R have recently been reported to drive the onset of chronic neutrophilic leukemia (CNL). Here we show that although truncation mutation alone can not induce leukemia, both proximal and compound mutations (proximal and truncation mutations on same allele) are leukemogenic with a disease latency of 90 and 23 days, respectively. Comparative whole-genome expression profiling and biochemical experiments revealed that induced expression of Mapk adaptor protein Ksr1 and enhanced Mapk signaling are crucial to leukemogenesis by CSF3R proximal and compound mutants. Moreover, inhibition of Mek1/2 by trametinib alone is sufficient to suppress leukemia induced by both CSF3R proximal and ruxolitinib-resistant compound mutations. Together, these findings elucidate a Mapk-dependent mechanism of CSF3R-induced pathogenesis, and they establish the rationale for clinical evaluation of MEK1/2 inhibition in CNL.
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影响因子：
15.9
作者：
McLemore, ML;Poursine-Laurent, J;Link, DC
通讯作者：
Link, DC
影响因子：
4.4
作者：
Komurov K;Dursun S;Erdin S;Ram PT
通讯作者：
Ram PT
DOI：
10.1056/nejmoa1214514
发表时间：
2013-05-09
期刊：
The New England journal of medicine
影响因子：
--
作者：
Maxson JE;Gotlib J;Pollyea DA;Fleischman AG;Agarwal A;Eide CA;Bottomly D;Wilmot B;McWeeney SK;Tognon CE;Pond JB;Collins RH;Goueli B;Oh ST;Deininger MW;Chang BH;Loriaux MM;Druker BJ;Tyner JW
通讯作者：
Tyner JW
影响因子：
20.3
作者：
Futami, Muneyoshi;Zhu, Quan-sheng;Corey, Seth J.
通讯作者：
Corey, Seth J.
影响因子：
4.4
作者：
Hunter, MG;Jacob, A;Avalos, BR
通讯作者：
Avalos, BR