Department of Genetics, Friedrich-Alexander-University Erlangen-Nürnberg.
Haematologica. 2022 Nov 1;107(11):2601-2616. doi: 10.3324/haematol.2022.280831.
The homeobox transcription factors HoxA9 and Meis1 are causally involved in the etiology of acute myeloid leukemia. While HoxA9 alone immortalizes cells, cooperation with Meis1 is necessary to induce a full leukemic phenotype. Here, we applied degron techniques to elucidate the leukemogenic contribution of Meis1. Chromatin immunoprecipitation experiments revealed that Meis1 localized mainly to H3K27 acetylated and H3K4 mono-methylated enhancers preactivated by HoxA9. Chromatin association of Meis1 required physical presence of HoxA9 and all Meis1 DNA interactions were rapidly lost after HoxA9 degradation. Meis1 controlled a gene expression pattern dominated by Myc, ribosome biogenesis and ribosomal RNA synthesis genes. While Myc accounted for the cell cycle stimulating effect of Meis1, overexpression of this oncogene alone did not accelerate leukemogenesis. Besides its effect on Myc, Meis1 induced transcription of ribosomal biogenesis genes. This was accompanied by an elevated resistance against inhibition of ribosomal RNA synthesis and translation, but without affecting steady-state protein synthesis. Finally, we demonstrate that HoxA9 and Meis1 proteins are stabilized by post-translational modification. Mutation of HoxA9/Meis1 phosphorylation sites or inhibition of casein kinase 2 lead to rapid protein degradation suggesting a potential pathway for pharmacological intervention.
同源盒转录因子 HoxA9 和 Meis1 是急性髓系白血病发病机制中的因果因子。虽然 HoxA9 本身可以使细胞永生化，但与 Meis1 合作是诱导完全白血病表型所必需的。在这里，我们应用降解结构域技术来阐明 Meis1 的致癌作用。染色质免疫沉淀实验表明，Meis1 主要定位于由 HoxA9 预先激活的 H3K27 乙酰化和 H3K4 单甲基化增强子上。Meis1 的染色质结合需要 HoxA9 的物理存在，并且在 HoxA9 降解后，所有 Meis1 DNA 相互作用都迅速丢失。Meis1 控制着一种以 Myc、核糖体生物发生和核糖体 RNA 合成基因为主导的基因表达模式。虽然 Myc 解释了 Meis1 的细胞周期刺激作用，但仅过表达这种癌基因并不能加速白血病的发生。除了对 Myc 的影响外，Meis1 还诱导了核糖体生物发生基因的转录。这伴随着对核糖体 RNA 合成和翻译抑制的抗性增加，但不影响稳态蛋白质合成。最后，我们证明 HoxA9 和 Meis1 蛋白通过翻译后修饰而稳定。HoxA9/Meis1 磷酸化位点的突变或酪蛋白激酶 2 的抑制导致蛋白质的快速降解，这表明存在潜在的药物干预途径。
