A DOMINANT MUTATION IN THE IKAROS GENE LEADS TO RAPID DEVELOPMENT OF LEUKEMIA AND LYMPHOMA
A DOMINANT MUTATION IN THE IKAROS GENE LEADS TO RAPID DEVELOPMENT OF LEUKEMIA AND LYMPHOMA
复制标题
DOI：
10.1016/0092-8674(95)90170-1
复制
发表时间：
1995-10-20
期刊：
影响因子：
64.5
通讯作者：
GEORGOPOULOS, K
中科院分区：
文献类型：
--
作者：
WINANDY, S;WU, P;GEORGOPOULOS, K
Ikaros 基因对于淋巴谱系规范至关重要。正如之前报道的，小鼠 Ikaros DNA 结合域的纯合 fora 突变无法产生成熟的淋巴细胞及其最早描述的祖细胞。此外，我们对这种突变杂合小鼠的研究表明，Ikaros 基因是 T 细胞增殖的重要调节因子。胸腺细胞表现出 TCR 介导的增殖反应增强，外周 T 细胞具有自身增殖能力。在所有杂合子中迅速发展的 T 细胞白血病和淋巴瘤之前，都会出现普遍的淋巴增殖。白血病转化的第一步发生在成熟的胸腺细胞群内，并通过克隆扩增和单个 Ikaros 野生型等位基因的丢失来划分。从这些研究中，我们提出，在发育中和成熟的 T 淋巴细胞中，需要不同的 Ikaros 活性阈值来调节增殖。 Ikaros 活性降低到第一阈值以下会导致 T 淋巴细胞快速积累，而进一步降低会导致肿瘤转化。
The Ikaros gene is essential for lymphoid lineage specification. As previously reported, mice homozygous fora mutation in the Ikaros DNA-binding domain fail to generate mature lymphocytes as well as their earliest described progenitors. In addition, our studies with mice heterozygous for this mutation establish the Ikaros gene as an essential regulator of T cell proliferation. Thymocytes display augmented TCR-mediated proliferative responses, and peripheral T cells are autoproliferative. A general lymphoproliferation precedes the T cell leukemia and lymphoma that rapidly develop in all heterozygotes. The first step toward leukemic transformation occurs within the maturing thymocyte population and is demarcated by clonal expansions and loss of the single Ikaros wild-type allele. From these studies, we propose that within developing and mature T lymphocytes, distinct thresholds of Ikaros activity are required to regulate proliferation. A decrease in Ikaros activity below the first threshold causes the rapid accumulation of T lymphoblasts, whereas a further decrease leads to neoplastic transformation.