Maki Kazuhiro, Yamagata Tetsuya, Asai Takashi, Yamazaki Ieharu, Oda Hideaki, Hirai Hisamaru, Mitani Kinuko
Department of Hematology, Dokkyo University School of Medicine, 880 Kitakobayashi, Mibu-machi, Shimotsuga-gun, Tochigi 321-0293, Japan.
Blood. 2005 Sep 15;106(6):2147-55. doi: 10.1182/blood-2004-11-4330. Epub 2005 May 24.
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 Aml1 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.
AML1/EVI1嵌合基因是由t(3;21)(q26;q22)染色体易位产生的，这种易位见于骨髓增生异常综合征白血病转化患者或慢性粒细胞白血病急变期患者。我们将AML1/EVI1嵌合基因敲入小鼠Aml1基因组位点，以探讨其在体内发育性造血中的作用。AML1/EVI1/+胚胎在胎肝中表现出造血缺陷，并在胚胎第13.5天（E13.5）左右因中枢神经系统出血而死亡。外周血中有卵黄囊来源的有核红细胞，但缺乏定型来源的红细胞。虽然E12.5胎肝仅含有巨噬细胞祖细胞，但E13.5胎肝含有能够分化为发育异常的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。与野生型肝脏来源的造血祖细胞相比，E13.5 AML1/EVI1/+胎肝来源的造血祖细胞具有高度的自我更新能力。PU.1基因的持续表达以及LMO2和SCL基因的表达降低可能解释了AML1/EVI1/+胎肝中的异常造血现象。
