Altered lymphoid development in mice deficient for the mAF4 proto-oncogene

作     者：Isnard, P Coré, N Naquet, P Djabali, M 

作者机构：CNRS INSERM Ctr Immunol F-13288 Marseille 9 France 

出 版 物：《BLOOD》 (血液)

年 卷 期：2000年第96卷第2期

页      面：705-710页

核心收录：

学科分类：1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 10[医学] 

主　　题：B淋巴细胞/生理学 骨髓细胞/生理学 CD4阳性T淋巴细胞/生理学 CD8阳性T淋巴细胞/生理学 DNA结合蛋白质类/缺乏 DNA结合蛋白质类/遗传学 糖皮质激素类/药理学 血细胞生成 淋巴细胞计数 淋巴细胞/生理学 小鼠 近交BALBC 小鼠 基因敲除 诱变 髓淋巴细胞性白血病蛋白质 核蛋白质类/缺乏 核蛋白质类/遗传学 原癌基因 T淋巴细胞/生理学 转录因子 转染 易位 遗传 动物 女(雌)性 男(雄)性 小鼠 

摘      要：Some chromosomal translocations in acute leukemias involve the fusion of the trithorax-related protein MII (also called HRX, All1, Htrx,) with a variety of heterologous proteins. In acute lymphoblastic leukemia associated with the t(4;11)(q21;q23) translocation, the 4q21 gene that fuses with MII is AF4, To gain insight into the potential role of AF4 in leukemogenesis and development, this gene was inactivated by homologous recombination in mice. As expected from the tissue distribution of the AF4 transcript, development of both B and T cells is affected in AF4 mutant mice. A severe reduction of the thymic double positive CD4/CD8 (CD4(+)/CD8(+)) population was observed;in addition most double- and single-positive cells expressed lower levels of CD4 and CD8 coreceptors, Most importantly, the reconstitution of the double-positive compartment by expansion of the double-negative cell compartment was severely impaired in these mutant mice. In the bone marrow pre-B and mature B-cell numbers are reduced. These results demonstrate that the function of the mAF4 gene is critical for normal lymphocyte development. This raises the possibility that the disruption of the normal AF4 gene or its association with MII function by translocation may orient the oncogenic process toward the lymphoid lineage. This represents the first functional study using a knock-out strategy on one of the Mil partner genes in translocation-associated leukemias.