PR 结构域蛋白 MDS1-EVI1 在 MLL-AF9 白血病中的必需作用。
Essential role of PR-domain protein MDS1-EVI1 in MLL-AF9 leukemia.
机构信息
Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY; and.
出版信息
Blood. 2013 Oct 17;122(16):2888-92. doi: 10.1182/blood-2012-08-453662. Epub 2013 Sep 10.
Abstract
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.
摘要
一组致白血病混合谱系白血病（MLL）融合蛋白（MFPs），包括 MLL-AF9，激活 Mecom 基因座并表现出极差的临床预后。Mecom 通过选择性转录起始位点编码 EVI1 和 MDS1-EVI1（ME）蛋白；这些蛋白的不同之处在于 ME 亚型中存在具有组蛋白甲基转移酶活性的 PRDI-BF1-RIZ1（PR）结构域。使用 ME 缺失的小鼠，我们表明 ME 在体外和体内均是 MLL-AF9 诱导转化所必需的。而且，尽管 Nup98-HOXA9、MEIS1-HOXA9 和 E2A-Hlf 可以转化 ME 缺失的细胞，但 MLL-AF9 和 MLL-ENL 均无效，表明 ME 的需求是特定于 MLL 融合白血病的。此外，我们表明 PR 结构域对于 MFP 诱导的转化是必需的。这些研究清楚地表明 PR 结构域蛋白 ME 在 MFP 白血病中的重要作用，表明 ME 可能是该组白血病治疗干预的新靶点。
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