Abramson Family Cancer Research Institute, Department of Cancer Biology, University of Pennsylvania, Philadelphia, 19104, USA.
Cancer Cell. 2010 Feb 17;17(2):148-59. doi: 10.1016/j.ccr.2009.12.034.
Oncogenic fusion proteins are capable of initiating tumorigenesis, but the role of their wild-type counterparts in this process is poorly understood. The mixed lineage leukemia (MLL) gene undergoes chromosomal translocations, resulting in the formation of oncogenic MLL fusion proteins (MLL-FPs). Here, we show that menin recruits both wild-type MLL and oncogenic MLL-AF9 fusion protein to the loci of HOX genes to activate their transcription. Wild-type MLL not only catalyzes histone methylation at key target genes but also controls distinct MLL-AF9-induced histone methylation. Notably, the wild-type Mll allele is required for MLL-AF9-induced leukemogenesis and maintenance of MLL-AF9-transformed cells. These findings suggest an essential cooperation between an oncogene and its wild-type counterpart in MLL-AF9-induced leukemogenesis.
致癌融合蛋白能够引发肿瘤发生，但人们对其野生型对应物在这一过程中的作用知之甚少。混合谱系白血病 (MLL) 基因发生染色体易位，导致致癌性 MLL 融合蛋白 (MLL-FP) 的形成。在这里，我们表明，menin 将野生型 MLL 和致癌性 MLL-AF9 融合蛋白募集到 HOX 基因的位置，以激活它们的转录。野生型 MLL 不仅催化关键靶基因的组蛋白甲基化，还控制不同的 MLL-AF9 诱导的组蛋白甲基化。值得注意的是，野生型 Mll 等位基因是 MLL-AF9 诱导的白血病发生和维持 MLL-AF9 转化细胞所必需的。这些发现表明，在 MLL-AF9 诱导的白血病发生中，致癌基因与其野生型对应物之间存在着至关重要的合作关系。
