Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Blood. 2012 Feb 2;119(5):1151-61. doi: 10.1182/blood-2011-06-362079. Epub 2011 Dec 15.
Mixed lineage leukemia (MLL) is a key epigenetic regulator of normal hematopoietic development and chromosomal translocations involving MLL are one of the most common genetic alterations in human leukemia. Here we show that ASB2, a component of the ECS(ASB) E3 ubiquitin ligase complex, mediates MLL degradation through interaction with the PHD/Bromodomain region of MLL. Forced expression of ASB2 degrades MLL and reduces MLL transactivation activity. In contrast, the MLL-AF9 fusion protein does not interact with ASB2 and is resistant to ASB2 mediated degradation. Increased expression of ASB2 during hematopoietic differentiation is associated with decreased levels of MLL protein and down-regulation of MLL target genes. Knockdown of ASB2 leads to increased expression of HOXA9 and delayed cell differentiation. Our data support a model whereby ASB2 contributes to hematopoietic differentiation, in part, through MLL degradation and HOX gene down-regulation. Moreover, deletion of the PHD/Bromo region renders MLL fusion proteins resistant to ASB2-mediated degradation and may contribute to leukemogenesis.
混合谱系白血病（MLL）是正常造血发育的关键表观遗传调节剂，涉及 MLL 的染色体易位是人类白血病中最常见的遗传改变之一。在这里，我们表明，ASB2 是 ECS（ASB）E3 泛素连接酶复合物的一个组成部分，通过与 MLL 的 PHD/Bromo 结构域相互作用来介导 MLL 的降解。ASB2 的强制表达会降解 MLL 并降低 MLL 的转录激活活性。相比之下，MLL-AF9 融合蛋白不会与 ASB2 相互作用，并且对 ASB2 介导的降解具有抗性。在造血分化过程中，ASB2 的表达增加与 MLL 蛋白水平降低和 MLL 靶基因下调有关。ASB2 的敲低导致 HOXA9 的表达增加和细胞分化延迟。我们的数据支持这样一种模型，即 ASB2 通过 MLL 降解和 HOX 基因下调，部分促进造血分化。此外，PHD/Bromo 区域的缺失使 MLL 融合蛋白对 ASB2 介导的降解具有抗性，可能有助于白血病的发生。
