Leukemogenesis caused by incapacitated GATA-1 function
Leukemogenesis caused by incapacitated GATA-1 function
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DOI：
10.1128/mcb.24.24.10814-10825.2004
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发表时间：
2004-12-01
影响因子：
5.3
通讯作者：
Yamamoto, M
中科院分区：
文献类型：
--
作者：
Shimizu, R;Kuroha, T;Yamamoto, M
加塔-1对于红系和巨核细胞谱系的发育是必需的。我们发现，加塔-1基因敲除雌性（加塔-1.05/X）小鼠经常发生类似骨髓增生异常综合征的造血系统疾病，其特征在于表达低水平加塔-1的祖细胞的积累。在这项研究中，我们证明，加塔-1.05/X小鼠患有两种不同类型的急性白血病，早发性c-Kit阳性非淋巴细胞白血病和迟发性B淋巴细胞白血病。由于加塔-1是X染色体基因，因此在杂合加塔-1敲除小鼠中存在两种类型的造血细胞，所述小鼠携带活性野生型加塔-1等位基因或活性突变型加塔-1.05等位基因。在具有后一种等位基因的造血祖细胞中，低水平的加塔-1表达足以支持存活和增殖，但不支持分化，导致容易被致癌刺激物靶向的祖细胞的积累。由于在加塔-1-null/X突变小鼠中没有观察到这种白血病，我们得出结论，敲除小鼠中残留的GATA-I活性有助于恶性肿瘤的发展。这种从头模型概括了在人类白血病前状态中发现的急性危象。
GATA-1 is essential for the development of erythroid and megakaryocytic lineages. We found that GATA-1 gene knockdown female (GATA-1.05/X) mice frequently develop a hematopoietic disorder resembling myelodysplastic syndrome that is characterized by the accumulation of progenitors expressing low levels of GATA-1. In this study, we demonstrate that GATA-1.05/X mice suffer from two distinct types of acute leukemia, an early-onset c-Kit-positive nonlymphoid leukemia and a late-onset B-lymphocytic leukemia. Since GATA-1 is an X chromosome gene, two types of hematopoietic cells reside within heterozygous GATA-1 knockdown mice, bearing either an active wild-type GATA-1 allelle or an active mutant GATA-1.05 allele. In the hematopoietic progenitors with the latter allele, low-level GATA-1 expression is sufficient to support survival and proliferation but not differentiation, leading to the accumulation of progenitors that are easily targeted by oncogenic stimuli. Since such leukemia has not been observed in GATA-1-null/X mutant mice, we conclude that the residual GATA-I activity in the knockdown mice contributes to the development of the malignancy. This de novo model recapitulates the acute crisis found in preleukemic conditions in humans.