Dysplastic definitive hematopoiesis in AML1/EVI1 knock-in embryos
Dysplastic definitive hematopoiesis in AML1/EVI1 knock-in embryos
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DOI：
10.1182/blood-2004-11-4330
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发表时间：
2005-09-15
期刊：
影响因子：
20.3
通讯作者：
Mitani, K
中科院分区：
文献类型：
--
作者：
Maki, K;Yamagata, T;Mitani, K
AML 1/EVI 1嵌合基因是由t（3;21）（q26;q22）染色体易位产生的，见于骨髓增生异常综合征的白血病转化或慢性粒细胞白血病的急变患者。我们将AML 1/EVI 1嵌合基因敲入小鼠AmI 1基因组，以探讨其在体内发育造血中的作用。AML 1/EVI 1/（+）胚胎在胚胎13.5天（E13.5）左右由于中枢神经系统出血而死亡。外周血有卵黄囊来源的有核成红细胞，但缺乏确定来源的红细胞。虽然E12.5胎肝仅含有巨噬细胞的祖细胞，但E13.5胎肝含有能够分化为发育不良的骨髓细胞和巨核细胞的多系祖细胞。在E12.5或E13.5胎肝中未检测到红系祖细胞。E13.5 AML 1/EVI 1/（+）胎肝造血祖细胞较野生型胎肝造血祖细胞具有更强的自我更新能力。PU.1基因的持续表达和LMO 2、SCL基因的低表达可能是AML 1/EVI 1/（+）胎肝造血异常的原因。
The AML1/EVI1 chimeric gene is created by the t(3;21)(q26;q22) chromosomal translocation seen in patients with leukemic transformation of myelodysplastic syndrome or blastic crisis of chronic myelogenous leukemia. We knocked-in the AML1/EVI1 chimeric gene into mouse AmI1 genomic locus to explore its effect in developmental hematopoiesis in vivo. AML1/EVI1/(+) embryo showed defective hematopoiesis in the fetal liver and died around embryonic day 13.5 (E13.5) as a result of hemorrhage in the central nervous system. The peripheral blood had yolk-sac-derived nucleated erythroblasts but lacked erythrocytes of the definitive origin. Although E12.5 fetal liver contained progenitors for macrophage only, E13.5 fetal liver contained multilineage progenitors capable of differentiating into dysplastic myelocyte and megakaryocyte. No erythroid progenitor was detected in E12.5 or E13.5 fetal liver. Hematopoietic progenitors from E13.5 AML1/ EVI1/(+) fetal liver were highly capable of self-renewal compared with those from wild-type liver. Maintained expression of PU.1 gene and decreased expression of LMO2 and SCL genes may explain the aberrant hematopoiesis in AML1/EVI1/(+) fetal liver.