Helen Diller Family Comprehensive Cancer Center and Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94143, USA.
J Exp Med. 2010 Nov 22;207(12):2581-94. doi: 10.1084/jem.20091071. Epub 2010 Nov 8.
Gain of chromosome 8 is the most common chromosomal gain in human acute myeloid leukemia (AML). It has been hypothesized that gain of the MYC protooncogene is of central importance in trisomy 8, but the experimental data to support this are limited and controversial. In a mouse model of promyelocytic leukemia in which the MRP8 promoter drives expression of the PML-RARA fusion gene in myeloid cells, a Myc allele is gained in approximately two-thirds of cases as a result of trisomy for mouse chromosome 15. We used this model to test the idea that MYC underlies acquisition of trisomy in AML. We used a retroviral vector to drive expression of wild-type, hypermorphic, or hypomorphic MYC in bone marrow that expressed the PML-RARA transgene. MYC retroviruses cooperated in myeloid leukemogenesis and suppressed gain of chromosome 15. When the PML-RARA transgene was expressed in a Myc haploinsufficient background, we observed selection for increased copies of the wild-type Myc allele concomitant with leukemic transformation. In addition, we found that human myeloid leukemias with trisomy 8 have increased MYC. These data show that gain of MYC can contribute to the pathogenic effect of the most common trisomy of human AML.
8 号染色体获得是人类急性髓性白血病（AML）中最常见的染色体获得。人们假设，MYC 原癌基因的获得在 8 号三体中具有重要意义，但支持这一假说的实验数据有限且存在争议。在一个髓系白血病的小鼠模型中，MRP8 启动子驱动髓系细胞中 PML-RARA 融合基因的表达，大约三分之二的病例由于小鼠染色体 15 的三体而获得 Myc 等位基因。我们利用这个模型来检验 MYC 是 AML 三体获得的基础这一观点。我们使用逆转录病毒载体在表达 PML-RARA 转基因的骨髓中驱动野生型、超活力型或低活力型 MYC 的表达。MYC 逆转录病毒在髓系白血病发生中合作，并抑制 15 号染色体的获得。当 PML-RARA 转基因在 Myc 半合子不足的背景下表达时，我们观察到与白血病转化同时发生的野生型 Myc 等位基因拷贝数增加的选择。此外，我们发现具有 8 号三体的人类髓性白血病中 MYC 增加。这些数据表明，MYC 的获得可能有助于人类 AML 最常见的三体的致病效应。
