AML-1 is required for megakaryocytic maturation and lymphocytic differentiation, but not for maintenance of hematopoietic stem cells in adult hematopoiesis
AML-1 is required for megakaryocytic maturation and lymphocytic differentiation, but not for maintenance of hematopoietic stem cells in adult hematopoiesis
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DOI：
10.1038/nm997
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发表时间：
2004-03-01
期刊：
影响因子：
82.9
通讯作者：
Kurokawa, M
中科院分区：
文献类型：
--
作者：
Ichikawa, M;Asai, T;Kurokawa, M
多谱系造血的胚胎发育需要谱系特异性转录因子的精确调控表达，包括AML - 1（由Runx1编码；也称为CBFA - 2或PEBP - 2αB）（1 - 5）。体外研究以及在包括白血病（6，7）、骨髓增生异常综合征8和易患急性髓系白血病（AML）的家族性血小板疾病（9）等人类疾病中的发现表明，AML - 1在成人造血中具有关键作用。然而，由于Runx1基因敲除小鼠在胚胎期致死，这一作用在体内尚未完全阐明。在此，我们使用一种诱导性基因靶向方法10评估AML - 1/Runx1在成人造血中的需求。在缺乏AML - 1的情况下，造血祖细胞完全得以维持，且髓系细胞发育正常。然而，AML - 1缺陷型骨髓显示巨核细胞成熟受抑制，造血祖细胞增多以及T和B淋巴细胞发育缺陷。因此，在成人造血中，AML - 1是巨核细胞成熟以及T细胞和B细胞分化所必需的，但对于造血干细胞（HSCs）的维持不是必需的。
Embryonic development of multilineage hematopoiesis requires the precisely regulated expression of lineage-specific transcription factors, including AML-1 (encoded by Runx1; also known as CBFA-2 or PEBP-2alphaB)(1-5). In vitro studies and findings in human diseases, including leukemias(6,7), myelodysplastic syndromes 8 and familial platelet disorder with predisposition to acute myeloid leukemia (AML)(9), suggest that AML-1 has a pivotal role in adult hematopoiesis. However, this role has not been fully uncovered in vivo because of the embryonic lethality of Runx1 knockout in mice. Here we assess the requirement of AML-1/Runx1 in adult hematopoiesis using an inducible gene-targeting method 10. In the absence of AML-1, hematopoietic progenitors were fully maintained with normal myeloid cell development. However, AML-1-deficient bone marrow showed inhibition of megakaryocytic maturation, increased hematopoietic progenitor cells and defective T- and B-lymphocyte development. AML-1 is thus required for maturation of megakaryocytes and differentiation of T and B cells, but not for maintenance of hematopoietic stem cells (HSCs) in adult hematopoiesis.