Mamo Aline, Krosl Jana, Kroon Evert, Bijl Janet, Thompson Alexander, Mayotte Nadine, Girard Simon, Bisaillon Richard, Beslu Nathalie, Featherstone Mark, Sauvageau Guy
Laboratory of Molecular Genetics of Stem Cells, Institute of Research in Immunology and Cancer (IRIC), Université de Montréal, QC, Canada.
Blood. 2006 Jul 15;108(2):622-9. doi: 10.1182/blood-2005-06-2244. Epub 2006 Feb 9.
The Hoxa9 and Meis1 genes represent important oncogenic collaborators activated in a significant proportion of human leukemias with genetic alterations in the MLL gene. In this study, we show that the transforming property of Meis1 is modulated by 3 conserved domains, namely the Pbx interaction motif (PIM), the homeodomain, and the C-terminal region recently described to possess transactivating properties. Meis1 and Pbx1 interaction domain-swapping mutants are dysfunctional separately, but restore the full oncogenic activity of Meis1 when cotransduced in primary cells engineered to overexpress Hoxa9, thus implying a modular nature for PIM in Meis1-accelerated transformation. Moreover, we show that the transactivating domain of VP16 can restore, and even enhance, the oncogenic potential of the Meis1 mutant lacking the C-terminal 49 amino acids. In contrast to Meis1, the fusion VP16-Meis1 is spontaneously oncogenic, and all leukemias harbor genetic activation of endogenous Hoxa9 and/or Hoxa7, suggesting that Hoxa gene activation represents a key event required for the oncogenic activity of VP16-Meis1.
Hoxa9和Meis1基因是重要的致癌协同因子，在相当一部分MLL基因发生遗传改变的人类白血病中被激活。在本研究中，我们发现Meis1的转化特性受3个保守结构域调控，即Pbx相互作用基序（PIM）、同源结构域以及最近被描述具有反式激活特性的C端区域。Meis1和Pbx1相互作用结构域交换突变体单独时功能失调，但在经基因工程改造过表达Hoxa9的原代细胞中共转导时可恢复Meis1的全部致癌活性，这意味着PIM在Meis1加速转化过程中具有模块化性质。此外，我们发现VP16的反式激活结构域可恢复甚至增强缺失C端49个氨基酸的Meis1突变体的致癌潜能。与Meis1不同，融合蛋白VP16-Meis1具有自发致癌性，且所有白血病均存在内源性Hoxa9和/或Hoxa7的基因激活，这表明Hoxa基因激活是VP16-Meis1致癌活性所需的关键事件。
