Essential role of PR-domain protein MDS1-EVI1 in MLL-AF9 leukemia.
Essential role of PR-domain protein MDS1-EVI1 in MLL-AF9 leukemia.
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DOI：
10.1182/blood-2012-08-453662
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发表时间：
2013-10
期刊：
影响因子：
20.3
通讯作者：
Yi Zhang;Kristin S. Owens;Layla Hatem;C. Glass;Kannan Karuppaiah;F. Camargo;A. Perkins
中科院分区：
文献类型：
--
作者：
Yi Zhang;Kristin S. Owens;Layla Hatem;C. Glass;Kannan Karuppaiah;F. Camargo;A. Perkins
包括MLL - AF9在内的一组致白血病混合谱系白血病（MLL）融合蛋白（MFPs）可激活Mecom基因座，并呈现出极差的临床预后。Mecom通过不同的转录起始位点编码EVI1和MDS1 - EVI1（ME）蛋白；这两种蛋白的差异在于ME异构体中存在具有组蛋白甲基转移酶活性的PRDI - BF1 - RIZ1（PR）结构域。我们利用一种ME缺陷型小鼠证明，在体外和体内ME对于MLL - AF9诱导的转化都是必需的。并且，尽管Nup98 - HOXA9、MEIS1 - HOXA9和E2A - Hlf能够转化ME缺陷型细胞，但MLL - AF9和MLL - ENL均无效，这表明ME的需求对于MLL融合白血病是特异性的。此外，我们证明PR结构域对于MFP诱导的转化至关重要。这些研究清楚地表明PR结构域蛋白ME在MFP白血病中具有关键作用，提示ME可能是针对这类白血病进行治疗干预的一个新靶点。
A subgroup of leukemogenic mixed-lineage leukemia (MLL) fusion proteins (MFPs) including MLL-AF9 activates the Mecom locus and exhibits extremely poor clinical prognosis. Mecom encodes EVI1 and MDS1-EVI1 (ME) proteins via alternative transcription start sites; these differ by the presence of a PRDI-BF1-RIZ1 (PR) domain with histone methyltransferase activity in the ME isoform. Using an ME-deficient mouse, we show that ME is required for MLL-AF9-induced transformation both in vitro and in vivo. And, although Nup98-HOXA9, MEIS1-HOXA9, and E2A-Hlf could transform ME-deficient cells, both MLL-AF9 and MLL-ENL were ineffective, indicating that the ME requirement is specific to MLL fusion leukemia. Further, we show that the PR domain is essential for MFP-induced transformation. These studies clearly indicate an essential role of PR-domain protein ME in MFP leukemia, suggesting that ME may be a novel target for therapeutic intervention for this group of leukemias.