SEARCH AML1-ETO INTERACTING PROTEIN

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 T(8；21)(q22；q22)易位是急性髓系白血病(AML)最常见的遗传异常之一，占AML病例的15%，其中FAB M2亚型占40-50%，M0、M1和M4亚型罕见。这种易位最常见的AML1-ETO融合蛋白(全长AML1-ETO)由752个氨基酸组成，包含RUNX1(也称为AML1、CBFalpha2或PEBP2alphaB)的N端部分，包括其DNA结合域，以及几乎整个Runx1T1(也称为MTG8或ETO)蛋白。虽然已有报道AML1-ETO存在基因表达改变和造血细胞增殖，但其表达并不会导致白血病的发生。在这里，我们报告了之前未知的AML1-ETO转录本的另一种剪接异构体，AML1-ETO9a，它包括ETO基因的一个额外外显子，外显子9a。AML1-ETO9a编码一个C端截短的AML1-ETO蛋白，由575个氨基酸组成。在小鼠逆转录病毒转导-移植模型中，AML1-ETO9a的表达导致白血病的快速发展。更重要的是，AML1-ETO和AML1-ETO9a的共同表达导致AML的发病时间大大提前，并在更不成熟的阶段阻止了髓系细胞的分化。这些结果表明，来自染色体易位的选择性剪接异构体的融合蛋白可能共同作用，导致癌症的发生。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.