SALL4, a novel oncogene, is constitutively expressed in human acute myeloid leukemia (AML) and induces AML in transgenic mice
SALL4, a novel oncogene, is constitutively expressed in human acute myeloid leukemia (AML) and induces AML in transgenic mice
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DOI：
10.1182/blood-2006-02-001594
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发表时间：
2006-10-15
期刊：
影响因子：
20.3
通讯作者：
Chai, Li
中科院分区：
文献类型：
--
作者：
Ma, Yupo;Cui, Wei;Chai, Li
SALL 4是果蝇spalt的人类同源基因，是一种新的发育必需的锌指转录因子。我们克隆了SALL 4及其亚型（SALL 4A和SALL 4 B）。通过免疫组化和实时逆转录聚合酶链反应（RT-PCR），我们证明了SALL 4的组成型表达在人原发性急性髓细胞白血病（AML，n = 81），并直接测试了组成型表达的SALL 4在小鼠模型中的白血病发生潜力。SALL 4 B转基因小鼠出现骨髓增生异常综合征（MDS）样特征，随后出现可移植的AML。在转基因小鼠骨髓和集落形成（CFU）测定中，与骨髓生成障碍相关的细胞凋亡增加是明显的。两种亚型都能与β-catenin结合，协同增强Wnt/β-catenin信号通路。我们的数据表明，SALL 4的组成型表达导致MDS/AML，最有可能通过Wnt/β-连环蛋白途径。我们的小鼠模型为研究人类MDS/AML转化以及Wnt/β-连环蛋白通路在白血病干细胞发病机制中的作用提供了一个有用的平台。
SALL4, a human homolog to Drosophila spalt, is a novel zinc finger transcriptional factor essential for development. We cloned SALL4 and its isoforms (SALL4A and SALL4B). Through immunohistochemistry and real-time reverse-transcription-polymerase chain reaction (RT-PCR), we demonstrated that SALL4 was constitutively expressed in human primary acute myeloid leukemia (AML, n = 81), and directly tested the leukemogenic potential of constitutive expression of SALL4 in a murine model. SALL4B transgenic mice developed myelodysplastic syndrome (MDS)-like features and subsequently AML that was transplantable. Increased apoptosis associated with dysmyelopoiesis was evident in transgenic mouse marrow and colony-formation (CFU) assays. Both isoforms could bind to beta-catenin and synergistically enhanced the Wnt/beta-catenin signaling pathway. Our data suggest that the constitutive expression of SALL4 causes MDS/AML, most likely through the Wnt/beta-catenin pathway. Our murine model provides a useful platform to study human MDS/AML transformation, as well as the Wnt/beta-catenin pathway's role in the pathogenesis of leukemia stem cells.