Yan Ming, Kanbe Eiki, Peterson Luke F, Boyapati Anita, Miao Yuqin, Wang Yang, Chen I-Ming, Chen Zixing, Rowley Janet D, Willman Cheryl L, Zhang Dong-Er
Department of Molecular and Experimental Medicine, The Scripps Research Institute, MEM-L51, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Nat Med. 2006 Aug;12(8):945-9. doi: 10.1038/nm1443. Epub 2006 Jul 30.
The t(8;21)(q22;q22) translocation is one of the most common genetic abnormalities in acute myeloid leukemia (AML), identified in 15% of all cases of AML, including 40-50% of FAB M2 subtype and rare cases of M0, M1 and M4 subtypes. The most commonly known AML1-ETO fusion protein (full-length AML1-ETO) from this translocation has 752 amino acids and contains the N-terminal portion of RUNX1 (also known as AML1, CBFalpha2 or PEBP2alphaB), including its DNA binding domain, and almost the entire RUNX1T1 (also known as MTG8 or ETO) protein. Although alterations of gene expression and hematopoietic cell proliferation have been reported in the presence of AML1-ETO, its expression does not lead to the development of leukemia. Here, we report the identification of a previously unknown alternatively spliced isoform of the AML1-ETO transcript, AML1-ETO9a, that includes an extra exon, exon 9a, of the ETO gene. AML1-ETO9a encodes a C-terminally truncated AML1-ETO protein of 575 amino acids. Expression of AML1-ETO9a leads to rapid development of leukemia in a mouse retroviral transduction-transplantation model. More importantly, coexpression of AML1-ETO and AML1-ETO9a results in the substantially earlier onset of AML and blocks myeloid cell differentiation at a more immature stage. These results indicate that fusion proteins from alternatively spliced isoforms of a chromosomal translocation may work together to induce cancer development.
t(8;21)(q22;q22)易位是急性髓系白血病（AML）中最常见的基因异常之一，在所有AML病例中占15%，包括40 - 50%的FAB M2亚型以及罕见的M0、M1和M4亚型病例。这种易位最广为人知的AML1-ETO融合蛋白（全长AML1-ETO）有752个氨基酸，包含RUNX1（也称为AML1、CBFα2或PEBP2αB）的N端部分，包括其DNA结合结构域，以及几乎整个RUNX1T1（也称为MTG8或ETO）蛋白。尽管在存在AML1-ETO的情况下已报道有基因表达改变和造血细胞增殖，但它的表达并不会导致白血病的发生。在此，我们报告鉴定出一种先前未知的AML1-ETO转录本的可变剪接异构体AML1-ETO9a，它包含ETO基因的一个额外外显子，即外显子9a。AML1-ETO9a编码一种C端截短的含575个氨基酸的AML1-ETO蛋白。在小鼠逆转录病毒转导-移植模型中，AML1-ETO9a的表达会导致白血病快速发展。更重要的是，AML1-ETO和AML1-ETO9a的共表达会导致AML发病明显提前，并在更不成熟阶段阻断髓系细胞分化。这些结果表明，染色体易位的可变剪接异构体产生的融合蛋白可能共同作用诱导癌症发生。
