Multiple mixed lineage leukemia (MLL) fusion proteins suppress p53-mediated response to DNA damage
Multiple mixed lineage leukemia (MLL) fusion proteins suppress p53-mediated response to DNA damage
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DOI：
10.1074/jbc.m412237200
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发表时间：
2005-07-01
影响因子：
4.8
通讯作者：
Yuan, ZM
中科院分区：
文献类型：
--
作者：
Wiederschain, D;Kawai, H;Yuan, ZM
涉及混合谱系白血病（MLL）基因的染色体易位在髓系和淋巴细胞起源的急性白血病中经常观察到。已知MLL融合蛋白的表达可诱导正常血祖细胞的恶性转化；然而，这一过程的分子机制仍然知之甚少。在这项研究中，我们研究了几种经常检测到的MLL融合蛋白对p53转录活性的影响。我们的数据显示，MLL- AF9、MLL- AF10、MLL- ENL和MLL- ELL在DNA损伤时显著下调p53介导的p21、MDM2和Bax的表达。此外，我们发现p300降低p53乙酰化是MLL白血病融合抑制作用的主要机制。我们的数据表明p53功能活性的丧失可能是MLL融合介导的白血病发生的共同特征。
Chromosomal translocations involving the mixed lineage leukemia ( MLL) gene are often observed in acute leukemias of both myeloid and lymphocytic origin. Expression of MLL fusion proteins is known to induce malignant transformation of normal blood progenitors; however, molecular mechanisms of this process are still poorly understood. In this study we investigated the effect of several frequently detected MLL fusion proteins on p53 transcriptional activity. Our data show that MLL- AF9, MLL- AF10, MLL- ENL, and MLL- ELL substantially down- regulate p53- mediated induction of p21, MDM2, and Bax in response to DNA damage. Furthermore, we identify the reduction in p53 acetylation by p300 as a major mechanism of the inhibitory effect of MLL leukemic fusions. Our data suggest that abrogation of p53 functional activity can be a common feature of MLL fusion- mediated leukemogenesis.