急性髓細(xì)胞性白血病(acute myeloid leukemia, AML, 也譯作急性髓系白血病或急性髓性白血病)是成年人身上常見(jiàn)的一種白血病,，其特征在于癌性骨髓細(xì)胞(cancerous bone marrow cell)異常增殖。在急性髓細(xì)胞性白血病中,，人們觀察到的的最為流行的突變之一就是一種被稱作FLT3受體的蛋白受體存在激活突變,。FLT3突變體被認(rèn)為能夠激活促進(jìn)癌癥生長(zhǎng)的信號(hào)途徑。
來(lái)自美國(guó)波士頓市哈佛大學(xué)的Daniel Tenen博士和同事們發(fā)現(xiàn)FLT3突變激活的一種新途徑,。他們的研究結(jié)果表明一種細(xì)胞分裂的關(guān)鍵性調(diào)節(jié)分子,，細(xì)胞周期蛋白依賴性激酶1(cyclin dependent kinase 1, CDK1)，在FLT3發(fā)生突變的白血病中被激活,，從而導(dǎo)致下游的基因轉(zhuǎn)錄激活,。
更為重要的是,，他們證實(shí)抑制CDK1活性促進(jìn)來(lái)自病人外周血樣品的細(xì)胞分化。
鑒于利用CDK1抑制劑進(jìn)行的臨床試驗(yàn)正在進(jìn)行中,，他們的研究結(jié)果強(qiáng)烈地提示著靶向CDK1途徑的治療方法可能非常有效地治療攜帶FLT3突變的急性髓細(xì)胞性白血病,，特別是對(duì)那些對(duì)FLT3抑制劑療法產(chǎn)生耐藥性的病人而言，更是如此,。
相關(guān)研究結(jié)果于2012年7月16日發(fā)表在Journal of Clinical Investigation期刊上,。(生物谷：Bioon.com)
本文編譯自A new target in acute myeloid leukemia
doi:10.1172/JCI43354
PMC:
PMID:
Targeting CDK1 promotes FLT3-activated acute myeloid leukemia differentiation through C/EBPα
Hanna S. Radomska1, Meritxell Alberich-Jordà1,2, Britta Will1, David Gonzalez1, Ruud Delwel3 and Daniel G. Tenen
Mutations that activate the fms-like tyrosine kinase 3 (FLT3) receptor are among the most prevalent mutations in acute myeloid leukemias. The oncogenic role of FLT3 mutants has been attributed to the abnormal activation of several downstream signaling pathways, such as STAT3, STAT5, ERK1/2, and AKT. Here, we discovered that the cyclin-dependent kinase 1 (CDK1) pathway is also affected by internal tandem duplication mutations in FLT3. Moreover, we also identified C/EBPα, a granulopoiesis-promoting transcription factor, as a substrate for CDK1. We further demonstrated that CDK1 phosphorylates C/EBPα on serine 21, which inhibits its differentiation-inducing function. Importantly, we found that inhibition of CDK1 activity relieves the differentiation block in cell lines with mutated FLT3 as well as in primary patient–derived peripheral blood samples. Clinical trials with CDK1 inhibitors are currently under way for various malignancies. Our data strongly suggest that targeting the CDK1 pathway might be applied in the treatment of FLT3ITD mutant leukemias, especially those resistant to FLT3 inhibitor therapies.
