MLL fusion proteins preferentially regulate a subset of wild-type MLL target genes in the leukemic genome
MLL fusion proteins preferentially regulate a subset of wild-type MLL target genes in the leukemic genome
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MLL 融合蛋白优先调节白血病基因组中野生型 MLL 靶基因的子集
DOI：
10.1182/blood-2010-12-324699
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发表时间：
2011-06-23
期刊：
影响因子：
20.3
通讯作者：
Thirman, Michael J.
中科院分区：
文献类型：
--
作者：
Wang, Qian-fei;Wu, George;Thirman, Michael J.
MLL编码一种组蛋白甲基转移酶，在胚胎发育和造血过程中维持基因表达至关重要。11q23易位导致嵌合MLL融合蛋白的形成，这是急性白血病的有效驱动因素。然而，目前尚不清楚白血病基因组的哪一部分是由MLL融合体直接控制的。通过比较患者来源的白血病细胞系，我们发现MLL融合结合基因是野生型MLL识别的一小部分基因。在诱导型MLL- enl模型中，MLL融合蛋白结合和H3K79甲基化的变化仅限于基因组的特定部分，而野生型MLL分布在更大的基因位点上。令人惊讶的是，在223个mll - enl结合基因中，只有12个在融合蛋白诱导下mRNA表达显著增加。除了Hoxa9和Meis1，还包括Eya1和Six1，它们是在几种发育途径中重要的异二聚体转录因子。我们发现Eya1在体外具有使造血祖细胞永生化的能力，并与Six1合作进行造血转化试验。总之，我们的数据表明，MLL融合通过直接激活一小部分靶基因而促进急性白血病的发展。(血。2011;117 (25):6895 - 6905)
MLL encodes a histone methyltransferase that is critical in maintaining gene expression during embryonic development and hematopoiesis. 11q23 translocations result in the formation of chimeric MLL fusion proteins that act as potent drivers of acute leukemia. However, it remains unclear what portion of the leukemic genome is under the direct control of MLL fusions. By comparing patient-derived leukemic cell lines, we find that MLL fusion-bound genes are a small subset of that recognized by wild-type MLL. In an inducible MLL-ENL model, MLL fusion protein binding and changes in H3K79 methylation are limited to a specific portion of the genome, whereas wild-type MLL distributes to a much larger set of gene loci. Surprisingly, among 223 MLL-ENL-bound genes, only 12 demonstrate a significant increase in mRNA expression on induction of the fusion protein. In addition to Hoxa9 and Meis1, this includes Eya1 and Six1, which comprise a heterodimeric transcription factor important in several developmental pathways. We show that Eya1 has the capacity to immortalize hematopoietic progenitor cells in vitro and collaborates with Six1 in hematopoietic transformation assays. Altogether, our data suggest that MLL fusions contribute to the development of acute leukemia through direct activation of a small set of target genes. (Blood. 2011;117(25):6895-6905)