A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia.
A novel tumour-suppressor function for the Notch pathway in myeloid leukaemia.
复制标题
DOI：
10.1038/nature09999
复制
发表时间：
2011-05-12
期刊：
影响因子：
64.8
通讯作者：
Aifantis, Iannis
中科院分区：
文献类型：
--
作者：
Klinakis, Apostolos;Lobry, Camille;Abdel-Wahab, Omar;Oh, Philmo;Haeno, Hiroshi;Buonamici, Silvia;van De Walle, Inge;Cathelin, Severine;Trimarchi, Thomas;Araldi, Elisa;Liu, Cynthia;Ibrahim, Sherif;Beran, Miroslav;Zavadil, Jiri;Efstratiadis, Argiris;Taghon, Tom;Michor, Franziska;Levine, Ross L.;Aifantis, Iannis
Notch信号是多种生物和组织类型分化的中心调节因子。其活性受多亚单位γ-分泌酶复合体(γSE)控制。尽管Notch信号在实体瘤中可以同时发挥致癌和抑瘤作用，但在造血系统中，它是唯一的致癌信号，特别是在T细胞急性淋巴细胞白血病(T-ALL)中，T-ALL是一种以Notch1激活突变为特征的疾病。在这里，我们在部分慢性粒单核细胞白血病(CMML)患者中发现了新的体细胞失活Notch通路突变。小鼠造血干细胞(HSC)Notch信号失活导致粒/单核细胞(GMP)异常聚集，髓外造血，并诱发CMML样病。转录组分析显示，Notch信号通过Notch靶标Hes1直接抑制基因转录，调节广泛的粒单核细胞特异性基因信号。我们的研究确定了Notch信号在早期造血干细胞分化中的新作用，并表明Notch信号通路在同一组织中既可以起到促进肿瘤的作用，也可以起到抑制作用。
Notch signaling is a central regulator of differentiation in a variety of organisms and tissue types. Its activity is controlled by the multi-subunit γ–secretase complex (γSE) complex. Although Notch signaling can play both oncogenic and tumor suppressor roles in solid tumors, in the hematopoietic system, it is exclusively oncogenic, notably in T cell acute lymphoblastic leukemia (T-ALL), a disease characterized by Notch1 activating mutations. Here we identify novel somatic inactivating Notch pathway mutations in a fraction of chronic myelomonocytic leukemia (CMML) patients. Inactivation of Notch signaling in mouse hematopoietic stem cells (HSC) resulted in an aberrant accumulation of granulocyte/monocyte progenitors (GMP), extramedullary hematopoieisis and the induction of CMML-like disease. Transcriptome analysis revealed that Notch signaling regulates an extensive myelomonocytic-specific gene signature, through the direct suppression of gene transcription by the Notch target Hes1. Our studies identify a novel role for Notch signaling during early hematopoietic stem cell differentiation and suggest that the Notch pathway can play both tumor-promoting and suppressive roles within the same tissue.
登录
查看更多内容
影响因子：
23.9
作者：
Mercher T;Cornejo MG;Sears C;Kindler T;Moore SA;Maillard I;Pear WS;Aster JC;Gilliland DG
通讯作者：
Gilliland DG
影响因子：
3.7
作者：
Dumortier A;Durham AD;Di Piazza M;Vauclair S;Koch U;Ferrand G;Ferrero I;Demehri S;Song LL;Farr AG;Leonard WJ;Kopan R;Miele L;Hohl D;Finke D;Radtke F
通讯作者：
Radtke F
影响因子：
32.4
作者：
Radtke, F;Wilson, A;Aguet, M
通讯作者：
Aguet, M
影响因子：
9.8
作者：
Demehri S;Liu Z;Lee J;Lin MH;Crosby SD;Roberts CJ;Grigsby PW;Miner JH;Farr AG;Kopan R
通讯作者：
Kopan R
影响因子：
11.4
作者：
Robert-Moreno, Alex;Guiu, Jordi;Bigas, Anna
通讯作者：
Bigas, Anna