TEL-AML1相关儿童白血病中的起始细胞和癌症增殖细胞

Initiating and cancer-propagating cells in TEL-AML1-associated childhood leukemia.

作者信息

Hong Dengli, Gupta Rajeev, Ancliff Philip, Atzberger Ann, Brown John, Soneji Shamit, Green Joanne, Colman Sue, Piacibello Wanda, Buckle Veronica, Tsuzuki Shinobu, Greaves Mel, Enver Tariq

机构信息

Medical Research Council (MRC) Molecular Haematology Unit, Weatherall Institute for Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.

出版信息

Science. 2008 Jan 18;319(5861):336-9. doi: 10.1126/science.1150648.

DOI:10.1126/science.1150648

PMID:18202291

Abstract

Understanding cancer pathogenesis requires knowledge of not only the specific contributory genetic mutations but also the cellular framework in which they arise and function. Here we explore the clonal evolution of a form of childhood precursor-B cell acute lymphoblastic leukemia that is characterized by a chromosomal translocation generating a TEL-AML1 fusion gene. We identify a cell compartment in leukemic children that can propagate leukemia when transplanted in mice. By studying a monochorionic twin pair, one preleukemic and one with frank leukemia, we establish the lineal relationship between these "cancer-propagating" cells and the preleukemic cell in which the TEL-AML1 fusion first arises or has functional impact. Analysis of TEL-AML1-transduced cord blood cells suggests that TEL-AML1 functions as a first-hit mutation by endowing this preleukemic cell with altered self-renewal and survival properties.

摘要

了解癌症发病机制不仅需要知晓特定的致病变异基因，还需要了解这些基因产生及发挥作用的细胞框架。在此，我们探究了一种儿童前体B细胞急性淋巴细胞白血病的克隆进化，其特征是发生染色体易位，产生TEL-AML1融合基因。我们在患白血病儿童中识别出一个细胞区室，将其移植到小鼠体内时可引发白血病。通过研究一对单绒毛膜双胞胎，其中一个处于白血病前期，另一个患有明显的白血病，我们确定了这些“癌症增殖”细胞与首次出现TEL-AML1融合或产生功能影响的白血病前期细胞之间的谱系关系。对转导了TEL-AML1的脐血细胞的分析表明，TEL-AML1作为首个致病变异，赋予了这种白血病前期细胞改变的自我更新和存活特性。