4月6日,，國際著名學(xué)術(shù)期刊《血液》在線發(fā)表了中國科學(xué)院上海生命科學(xué)研究院/上海交通大學(xué)醫(yī)學(xué)院健康科學(xué)研究所發(fā)育與疾病實(shí)驗(yàn)室及瑞金醫(yī)院醫(yī)學(xué)基因組學(xué)國家重點(diǎn)實(shí)驗(yàn)室的最新研究發(fā)現(xiàn)：進(jìn)化上高度保守的PTEN-C/EBPa-CTNNA1信號軸控制造血干細(xì)胞發(fā)育與白血病干細(xì)胞惡性轉(zhuǎn)化,。
該實(shí)驗(yàn)室前期研究表明CTNNA1基因（編碼alpha-catenin蛋白）在正常造血干細(xì)胞表達(dá),，但在伴有5號染色體長臂缺失的骨髓增生異常綜合癥和急性髓系白血病患者的白血病干細(xì)胞（或白血病起始細(xì)胞）中表達(dá)水平顯著降低,。初步證據(jù)表明CTNNA1基因是一個(gè)潛在的白血病干細(xì)胞腫瘤抑制基因,，其一個(gè)等位基因通過基因組片段缺失而失活,，另外一個(gè)等位基因被表觀遺傳學(xué)機(jī)制(DNA甲基化和組蛋白去乙?；?抑制,。因?yàn)镈NA甲基化酶抑制劑和組蛋白去乙?；敢种苿┰谂R床上治療效果有限，因而進(jìn)一步尋找CTNNA1失活的表觀遺傳學(xué)機(jī)制和上游信號調(diào)節(jié)路徑對于在白血病干細(xì)胞中重新開啟此基因,，因而特異性靶向治療白血病腫瘤干細(xì)胞而不影響正常造血干細(xì)胞,，具有重要的基礎(chǔ)和臨床意義。
在健康所劉廷析研究員指導(dǎo)下,，通過和美國Loyola大學(xué)張吉旺教授及瑞金醫(yī)院諸江教授合作,，傅春堂和朱康勇等研究人員發(fā)現(xiàn)PTEN-mTOR信號通路作用在PTEN-C/EBPa-CTNNA1軸的上游，在翻譯水平?jīng)Q定野生型p42C/EBPa與其顯性負(fù)p30C/EBPa的比例：mTOR活性增加導(dǎo)致p42C/EBPa/p30C/EBPa比例下降,；mTOR活性減低導(dǎo)致p42C/EBPa/p30C/EBPa比例上升,。低的p42/p30比例導(dǎo)致p30C/EBPa優(yōu)先結(jié)合到CTNNA1基因的近端啟動子元件，并進(jìn)而招募含EZH2,，EED和SUZ12的PRC2蛋白復(fù)合體,，介導(dǎo)組蛋白H3在第27位賴氨酸殘基的三甲基化修飾（H3K27me3）和轉(zhuǎn)錄抑制。與此相反,，高的p42/p30比例則導(dǎo)致p42C/EBPa結(jié)合到CTNNA1基因的近端啟動子元件,，通過促進(jìn)H3K4三甲基化（H3K4me3）修飾激活CTNNA1轉(zhuǎn)錄。進(jìn)一步研究發(fā)現(xiàn),，在PTEN敲除的小鼠骨髓和Pten敲低的斑馬魚胚胎中,，野生型C/EBPa和alpha-catenin蛋白水平均顯著下調(diào),，同時(shí)伴有造血干祖細(xì)胞的白血病樣增生和異常浸潤。更重要的是,，該研究發(fā)現(xiàn)臨床上約20％的髓系白血病患者的白血病干細(xì)胞存在CTNNA1低水平表達(dá),，而PTEN或CEBPA的移碼突變只在這些CTNNA1表達(dá)低的白血病干細(xì)胞中被檢測。
這項(xiàng)研究揭示三個(gè)重要的白血病腫瘤抑制基因共同作用在一個(gè)進(jìn)化上高度保守的信號轉(zhuǎn)導(dǎo)軸中,，通過調(diào)節(jié)表觀遺傳學(xué)機(jī)制“三把鎖”（組蛋白H3K27甲基化,，組蛋白去乙酰化和DNA甲基化）而控制造血干細(xì)胞發(fā)育與白血病干細(xì)胞惡性轉(zhuǎn)化,。該白血病干細(xì)胞腫瘤抑制軸的發(fā)現(xiàn)也為白血病干細(xì)胞的靶向治療（特別是CTNNA1表達(dá)低的患者）提供了重要線索。
相關(guān)研究目前已申請專利,。該項(xiàng)目得到科技部發(fā)育與生殖重大科學(xué)研究計(jì)劃,，中科院百人計(jì)劃和國家杰出青年基金及上海市科委的資助。(生物谷Bioon.com)
延伸閱讀
Circulation：運(yùn)動有助于保持白細(xì)胞端粒長度
Nature Medicine：白細(xì)胞利用“DNA彈弓”抵御細(xì)菌感染
癌癥干細(xì)胞專題
干細(xì)胞專題（stem cell）專題
干細(xì)胞之春——生物谷盤點(diǎn)2009
2010干細(xì)胞技術(shù)與應(yīng)用講座即將隆重登場
生物谷推薦原文出處：
Blood DOI 10.1182/blood-2009-11-255778.
An evolutionarily conserved PTEN-C/EBP-CTNNA1 axis controls myeloid development and transformation
Chun-Tang Fu1, Kang-Yong Zhu1, Jian-Qing Mi1, Yuan-Fang Liu1, Susan T. Murray2, Yan-Fang Fu1, Chun-Guang Ren1, Zhi-Wei Dong1, Yi-Jie Liu1, Mei Dong1, Yi Jin1, Yi Chen1, Min Deng1, Wu Zhang1, Bin Chen1, Peter Breslin3, Sai-Juan Chen1, Zhu Chen1, Michael W. Becker2, Jiang Zhu1, Ji-Wang Zhang3 and Ting Xi Liu4,*
1 Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai, China; 2 Division of Hematology/Oncology, University of Rochester, Rochester, NY, United States; 3 Pathology Department, Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, IL, United States; 4 Shanghai Stem Cell Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Loss of function of tumor suppressor genes such as PTEN, C/EBPA and CTNNA1 has been found to play essential roles in leukemogenesis. However, whether these genes genetically interact remains unknown. We previously reported that the CTNNA1 gene is expressed at a very low level in the HL-60 cell line and in primary leukemia-initiating cells (LICs) with a 5q deletion. Here, we show that PTEN-mTOR signaling acts upstream to dictate the ratio of wild-type p42 C/EBP to its dominant-negative p30 isoform, which critically determines whether p30 C/EBP (lower p42/p30 ratio) or p42 C/EBP (higher p42/p30 ratio) binds to the proximal promoter of the retained CTNNA1 allele. Binding of p30 C/EBP recruits the PRC2 complex to suppress CTNNA1 transcription through repressive H3K27me3 modification, whereas binding of p42 C/EBP relieves this repression and promotes CTNNA1 expression through activating H3K4me3 modification. Loss of Pten function in mice and zebrafish induces myelodysplasia with abnormal invasiveness of myeloid progenitors accompanied by significant reductions in both wild-type C/EBP and -catenin protein. Importantly, frame-shift mutations in either PTEN or CEBPA were detected exclusively in the primary LICs with low CTNNA1 expression. This study uncovers a novel molecular pathway, PTEN-C/EBP-CTNNA1, which might be therapeutically targeted to eradicate LICs with low CTNNA1 expression.
