Defects in yolk sac hematopoiesis in Mll-null embryos
Defects in yolk sac hematopoiesis in Mll-null embryos
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DOI：
10.1182/blood.v90.5.1799
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发表时间：
1997-09-01
期刊：
影响因子：
20.3
通讯作者：
Korsmeyer, SJ
中科院分区：
文献类型：
--
作者：
Hess, JL;Yu, BD;Korsmeyer, SJ
涉及混合谱系白血病基因（MLL）的易位，是果蝇基因三胸的人类同源物，是人类急性白血病中最常见的遗传改变之一。涉及MLL的每个易位导致MLL的一个功能拷贝的丢失和具有潜在显性负或新变体活性的嵌合融合蛋白的产生。MII是Hox基因的正调控因子，Hox基因与中轴骨架形成和造血发育有关。先前的研究表明，Hox基因表达在MII杂合（+/-）和纯合（-/-）缺陷小鼠中改变。为了研究MII在造血中的作用并获得对白血病发生的见解，我们通过MII +/+、+/和-/-卵黄囊祖细胞的体外分化来检查单倍不足或缺乏MII的影响。与野生型和杂合子相比，MII -/-集落数量较少，发育时间较长，所含细胞较少，形成集落形成单位-粒细胞、红细胞、巨噬细胞、巨核细胞在MII -/-培养中，CFU-GEMM、集落形成单位-巨噬细胞（CFU-M）和爆发形成单位-红系（BFU-E）的数量显著减少，而集落形成单位-红系（CFU-E）、粒细胞集落形成单位（CFU G）和粒细胞巨噬细胞集落形成单位（CFU GM）基本上不受影响。尽管存在的集落数量减少，但MII -/-培养物显示所有细胞类型没有成熟停滞的形态学证据。这些研究表明，MII是正常数量的造血祖细胞及其适当分化所必需的，特别是沿着骨髓和巨噬细胞途径。(C)1997年，美国血液学会。
Translocations involving the mixed lineage leukemia gene (MLL), the human homolog of the Drosophila gene trithorax, are one of the most common genetic alterations in human acute leukemias. Each translocation involving MLL results in loss of one functional copy of MLL and the generation of a chimeric fusion protein with potential dominant negative or neomorphic activity. MII is a positive regulator of Hox genes, which have been implicated in both axial skeleton patterning and hematopoietic development. Previous studies indicated that Hox gene expression is altered in Mll heterozygous (+/-) and homozygous (-/-) deficient mice, To study the role of MII in hematopoiesis and to obtain insights into leukemogenesis, we have examined the effects of haplo-insufficiency or absence of MII by in vitro differentiation of MII +/+, +/, and -/- yolk sac progenitor cells. MII -/- colonies were fewer in number, took longer to develop, and contained fewer cells than their wild-type and heterozygous counterparts, Formation of colony-forming unit-granulocyte, erythroid, macrophage, megakaryocyte (CFU-GEMM), colony-forming unit-macrophage (CFU-M), and burst-forming unit-erythroid (BFU-E) was markedly decreased in MII -/- cultures, while numbers of colony-forming unit-erythroid (CFU-E), colony-forming unit-granulocyte (CFU G), and colony-forming unit-granulocyte macrophage (CFU GM) were essentially unaffected. Despite the decreased numbers of colonies present, MII -/- cultures showed all cell types without morphologic evidence of maturation arrest. These studies indicate that MII is required for normal numbers of hematopoietic progenitors and their proper differentiation, especially along the myeloid and macrophage pathways. (C) 1997 by The American Society of Hematology.