Runx1/AML-1 Ranks as a Master Regulator of Adult Hematopoiesis
Runx1/AML-1 Ranks as a Master Regulator of Adult Hematopoiesis
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DOI：
10.4161/cc.3.6.951
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发表时间：
2004-04
期刊：
影响因子：
4.3
通讯作者：
M. Ichikawa;T. Asai;S. Chiba;M. Kurokawa;S. Ogawa
中科院分区：
文献类型：
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作者：
M. Ichikawa;T. Asai;S. Chiba;M. Kurokawa;S. Ogawa
Runx 1（AML-1）是一个与人类白血病发生有关的关键基因，最初发现于t（8;21）（q21;q22）白血病易位的21 q22断裂点，被认为与高达25%的人类白血病有关。它编码一个转录因子，与果蝇蛋白runt同源，并在造血系统的调节中起重要作用。一个基因破坏实验明确地表明Runx 1是确定的或成人型造血的建立所必需的。此外，大量体外研究和家族性血小板紊乱伴急性髓细胞性白血病（FPD/AML）易感性患者的发现有力地表明，它也致力于成年后造血系统的控制，尽管深入分析其在成人造血中的作用在很大程度上受到Runx 1过早致死的阻碍，最近，我们开发了条件性基因敲除小鼠，其中Runx 1在出生后的造血区室中特异性地被破坏，并剖析了其在成人造血中的作用。值得注意的是，在这些小鼠中，巨核细胞的成熟以及T和B淋巴细胞的发育严重受损，而造血祖细胞在外周和骨髓中维持甚至扩增，具有明显正常的髓系和红系分化。我们的研究结果清楚地表明了Runx 1在干细胞发育和维持中的不同需求，以及这种转录因子的多模式功能，这些功能是巨核细胞成熟和淋巴细胞发育所必需的，也为Runx 1如何深入细致地参与造血调控提供了新的见解。
Runx1 (AML-1) is a critical gene involved in human leukemogenesis, originallyidentified at the 21q22 breakpoint of the leukemic translocations of t(8;21)(q21;q22), and is thoughtto be involved in as much as 25% of human leukemia. It encodes a transcription factor that hasclose homology to a Drosophila protein, runt, and is found to play essential roles in regulation ofhematopoietic systems. Really a gene disruption experiment unequivocally shows that Runx1 isabsolutely required for the establishment of definitive or adult-type hematopoiesis. Moreover,accumulated evidence from a number of in vitro studies and findings in patients with familial plateletdisorder with predisposition to acute myelogenous leukemia (FPD/AML) strongly suggests that italso commits to the control of hematopoietic system in adult life, although the in depth analysis of itsroles in adult hematopoiesis has been largely hampered by premature lethality of Runx1-null animals.Recently we have developed conditional knockout mice in which Runx1 is disrupted specifically inhematopoietic compartments after birth and dissected its roles in adult hematopoiesis. Notably, inthese mice, maturation of megakaryocytes and development of both T and B lymphocytes wereseverely impaired, whereas hematopoietic progenitors were maintained or even expanded withapparently normal myeloid and erythroid differentiation in the periphery and bone marrow. Ourfindings clearly demonstrated differential requirement of Runx1 in stem cell development and in itsmaintenance together with multi-modal functions of this transcription factor that are criticallyrequired for maturation of megakaryocytes and lymphocyte development, also providing a novelinsight into how deeply and meticulously Runx1 is involved in regulation of mammalianhematopoiesis.