SEARCH AML1-ETO INTERACTING PROTEIN

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 t（8; 21）（q22; q22）易位是急性髓性白血病（AML）中最常见的遗传异常之一，在所有AML病例中鉴定出15%，包括40-50%的FAB M2亚型和罕见的M0、M1和M4亚型病例。来自该易位的最常见的AML 1-ETO融合蛋白（全长AML 1-ETO）具有752个氨基酸，并含有RUNX 1（也称为AML 1、CBFalpha 2或PEBP 2alphaB）的N-末端部分，包括其DNA结合结构域，以及几乎整个RUNX 1 T1（也称为MTG 8或ETO）蛋白。尽管在AML 1-ETO存在下已报告基因表达和造血细胞增殖的改变，但其表达不会导致白血病的发展。在这里，我们报告了一个以前未知的选择性剪接异构体的AML 1-ETO转录，AML 1-ETO 9a，其中包括一个额外的外显子，外显子9a，ETO基因的鉴定。AML 1-ETO 9a编码575个氨基酸的C-末端截短的AML 1-ETO蛋白。在小鼠逆转录病毒转导-移植模型中AML 1-ETO 9a的表达导致白血病的快速发展。更重要的是，AML 1-ETO和AML 1-ETO 9a的共表达导致AML的显著更早发作，并在更不成熟的阶段阻断骨髓细胞分化。这些结果表明，来自染色体易位的选择性剪接同种型的融合蛋白可能共同作用以诱导癌症发展。

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.