Acute leukemia with promyelocytic features in PML/RAR alpha transgenic mice
Acute leukemia with promyelocytic features in PML/RAR alpha transgenic mice
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DOI：
10.1073/pnas.94.10.5302
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发表时间：
1997-05-13
影响因子：
11.1
通讯作者：
Pandolfi, PP
中科院分区：
文献类型：
--
作者：
He, LZ;Tribioli, C;Pandolfi, PP
急性早幼粒细胞白血病（APL）与涉及17号染色体上维甲酸受体α（RAR α）基因座的相互染色体易位有关。在大多数情况下，RAR α易位并与位于15号染色体上的早幼粒细胞白血病（PML）基因融合，所产生的融合基因编码两种结构独特的PML/RAR α和RAR α/PML融合蛋白以及异常PML基因产物，其各自的致病作用尚未阐明。我们已经产生了转基因小鼠，其中PML/RAR α融合蛋白在骨髓-早幼粒细胞谱系中特异性表达。在它们生命的第一年，所有的PML/RAR α转基因小鼠都有异常的造血，最好描述为骨髓增生性疾病。在12和14个月的年龄之间，他们中的10%发展成一种急性白血病，在早幼粒细胞阶段分化阻滞，甚至在对维甲酸的反应中也与人类APL密切相似。我们的结果是体内PML/RAR α在APL发病机制中起关键作用的确凿证据。
Acute promyelocytic leukemia (APL) is associated with reciprocal chromosomal translocations involving the retinoic acid receptor alpha (RAR alpha) locus on chromosome 17. In the majority of cases, RAR alpha translocates and fuses with the promyelocytic leukemia (PML) gene located on chromosome 15, The resulting fusion genes encode the two structurally unique PML/RAR alpha and RAR alpha/PML fusion proteins as well as aberrant PML gene products, the respective pathogenetic roles of which have not been elucidated. We have generated transgenic mice in which the PML/RAR alpha fusion protein is specifically expressed in the myeloid-promyelocytic lineage. During their first year of life, all the PML/RAR alpha transgenic mice have an abnormal hematopoiesis that can best be described as a myeloproliferative disorder. Between 12 and 14 months of age, 10% of them develop a form of acute leukemia with a differentiation block at the promyelocytic stage that closely mimics human APL even in its response to retinoic acid, Our results are conclusive in vivo evidence that PML/RAR alpha plays a crucial role in the pathogenesis of APL.