生物谷報(bào)道：白血病又稱血癌，是一種造血組織的惡性疾病,。其特點(diǎn)是骨髓等造血組織中有大量白血病細(xì)胞無限制地增生,，并進(jìn)入外周血液，而正常血細(xì)胞的制造被明顯抑制,。盡管該病已經(jīng)成為年輕人的頭號(hào)惡性疾病“殺手”,，但它的深層病因至今仍未完全弄清。
近日,，來自歐洲分子生物學(xué)實(shí)驗(yàn)室（EMBL）,、EMBL―歐洲生物信息學(xué)研究所、美國(guó)哈佛大學(xué)以及瑞典隆德大學(xué)的科學(xué)家小組發(fā)現(xiàn)，當(dāng)利用遺傳工程方法將人類白血病患者的一種基因變異導(dǎo)入小鼠體內(nèi)后,，該變異會(huì)通過觸發(fā)先天遺傳程序引起白細(xì)胞不受控制地增殖,，從而導(dǎo)致急性白血病。這一研究成果對(duì)于白血病的治療具有重要意義,。相關(guān)論文發(fā)表在4月8日的《癌細(xì)胞》雜志上,。
人們知道，血細(xì)胞是由身體內(nèi)少量的多能干細(xì)胞分化而來的,，這些干細(xì)胞同時(shí)要進(jìn)行自我維持,。通常就是在該過程中，一些基因變異會(huì)進(jìn)行干擾,，并且促使導(dǎo)致白血病的特定血細(xì)胞無限擴(kuò)增,。
而在最新研究中，科學(xué)家證實(shí)了一種名為C/EBPa蛋白上發(fā)生的變異會(huì)導(dǎo)致急性髓系白血?。ˋML）,。此外，該變異的致病機(jī)理也讓研究人員們眼前一亮,。EMBL Claus Nerlov實(shí)驗(yàn)室的Peggy Kirstetter表示：“盡管患有AML的病人中有10%帶有該變異,，但科學(xué)家從未確定它能夠?qū)е掳籽 Ｍㄟ^在小鼠模型上精確重現(xiàn)這一人類基因變異,，我們現(xiàn)在證實(shí)了它確實(shí)是一種白血病成因,。”
研究人員發(fā)現(xiàn)，與通常認(rèn)為的促使惡性造血干細(xì)胞無限增殖不同,，C/EBPa蛋白變異對(duì)已經(jīng)部分分化的細(xì)胞起作用,。該變異能重組這些細(xì)胞，使其進(jìn)行自我更新,，并制造出無數(shù)的功能異常子細(xì)胞取代健康血細(xì)胞,，最終導(dǎo)致周身氧運(yùn)輸無力。
Nerlov表示：“這是首次在健康的血系統(tǒng)中產(chǎn)生非干細(xì)胞骨髓白血病,。這一發(fā)現(xiàn)對(duì)于人們理解白血病的發(fā)展和治療具有深遠(yuǎn)的影響,。”
科學(xué)家們通常認(rèn)為，變異是導(dǎo)致白血病的關(guān)鍵一步,，應(yīng)該作為藥物標(biāo)靶,。而Nerlov和同事確定出一種在自我更新白血病細(xì)胞中激活的遺傳程序，它同樣存在于由其他類型變異所導(dǎo)致的類似白血病中,。這說明,，導(dǎo)致自我更新及無限增殖的細(xì)胞變化是與變異類型獨(dú)立的。為了開發(fā)出更具普遍效力的藥物,，應(yīng)當(dāng)以不同癌癥干細(xì)胞的共同分子路徑作為標(biāo)靶,。（科學(xué)時(shí)報(bào)）
生物谷推薦原始出處：
Cancer Cell, Vol 13, 299-310, 08 April 2008
Article
Modeling of C/EBPα Mutant Acute Myeloid Leukemia Reveals a Common Expression Signature of Committed Myeloid Leukemia-Initiating Cells
Peggy Kirstetter,1,8 Mikkel B. Schuster,1,2,8 Oksana Bereshchenko,1 Susan Moore,1 Heidi Dvinge,3 Elke Kurz,1 Kim Theilgaard-Mönch,2 Robert Månsson,4 Thomas Å. Pedersen,1 Thomas Pabst,5 Evelin Schrock,6 Bo T. Porse,2 Sten Eirik W. Jacobsen,4 Paul Bertone,3 Daniel G. Tenen,7 and Claus Nerlov1,
1 European Molecular Biology Laboratory, Mouse Biology Unit, Monterotondo 00016, Italy
2 Laboratory for Gene Therapy Research, Copenhagen University Hospital, 2100 Copenhagen, Denmark
3 European Bioinformatics Institute, Wellcome Trust Genome Campus, Cambridge CB10 1SD, UK
4 Hematopoietic Stem Cell Laboratory, Lund Strategic Center for Stem Cell Biology and Cell Therapy, University of Lund, 22184 Lund, Sweden
5 Institute of Medical Oncology, University Hospital, Bern 3010, Switzerland
6 Institute for Clinical Genetics, Dresden University of Technology, 01307 Dresden, Germany
7 Harvard Institutes of Medicine, Boston, MA 02115, USA
Corresponding author
Claus Nerlov
[email protected]
Summary
Mutations in the CEBPA gene are present in 7%–10% of human patients with acute myeloid leukemia (AML). However, no genetic models exist that demonstrate their etiological relevance. To mimic the most common mutations affecting CEBPA—that is, those leading to loss of the 42 kDa C/EBPα isoform (p42) while retaining the 30kDa isoform (p30)—we modified the mouse Cebpa locus to express only p30. p30 supported the formation of granulocyte-macrophage progenitors. However, p42 was required for control of myeloid progenitor proliferation, and p42-deficient mice developed AML with complete penetrance. p42-deficient leukemia could be transferred by a Mac1+c-Kit+ population that gave rise only to myeloid cells in recipient mice. Expression profiling of this population against normal Mac1+c-Kit+ progenitors revealed a signature shared with MLL-AF9-transformed AML.
