Loss of MLL PHD finger 3 is necessary for MLL-ENL-induced hematopoietic stem cell immortalization.
Loss of MLL PHD finger 3 is necessary for MLL-ENL-induced hematopoietic stem cell immortalization.
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DOI：
10.1158/0008-5472.can-07-6514
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发表时间：
2008-08-01
期刊：
影响因子：
11.2
通讯作者：
Diaz MO
中科院分区：
文献类型：
--
作者：
Chen J;Santillan DA;Koonce M;Wei W;Luo R;Thirman MJ;Zeleznik-Le NJ;Diaz MO
MLL基因位点的互惠染色体易位导致新的融合蛋白的表达，如与白血病相关的MLL- enl。三个PHD指盒是MLL中高度保守的结构域之一，在所有融合蛋白中都不存在。该结构域已被证明与Cyp33相互作用，Cyp33是一种亲环蛋白，可促进hdac招募到MLL抑制结构域并介导HOX基因抑制。将MLL的第三个PHD指插入MLL- enl中，允许将Cyp33和随后的HDAC1招募到融合蛋白上。此外，PHD手指插入融合蛋白的表达以Cyp33依赖的方式介导HOXC8基因表达的下调。最后，在MLL-ENL中添加PHD手指结构域或单独添加第3个PHD手指结构域，在串联镀菌落试验中阻断融合蛋白的造血干细胞永生化潜能。只插入第一和第二中指没有这种效果。这些数据支持了Cyp33与MLL 3rd PHD手指的结合将MLL功能从反式激活切换到抑制的假设。在永生化MLL融合蛋白中，PHD指的缺失，加上ENL或其他伴生蛋白激活域的获得，使融合蛋白成为一个组成型反式激活子。这导致MLL靶基因组成性过表达，阻断干细胞承诺并促进干细胞更新，这可能是MLL相关白血病发生的第一步。
Reciprocal chromosomal translocations at the MLL gene locus result in expression of novel fusion proteins such as MLL-ENL associated with leukemia. The three PHD finger cassette, one of the highly conserved domains in MLL, is absent in all fusion proteins. This domain has been shown to interact with Cyp33, a cyclophilin which enhances the recruitment of HDACs to the MLL repression domain and mediates HOX gene repression. Insertion of the third PHD finger of MLL, into MLL-ENL allows the recruitment of Cyp33, and subsequently HDAC1, to the fusion protein. Furthermore, expression of the fusion protein with the PHD finger insertion mediates the down-regulation of the HOXC8 gene expression in a Cyp33 dependent manner. Finally, the addition of the PHD finger domain or the 3rd PHD finger alone, into MLL-ENL, blocks the hematopoietic-stem-cell immortalization potential of the fusion protein in serial plating colony assays. Insertion of only the 1st and 2nd PHD fingers has no such effect. These data support the hypothesis that the binding of Cyp33 to the MLL 3rd PHD finger switches the MLL function from trans-activation to repression. In the immortalizing MLL fusion protein, the loss of the PHD fingers, in combination with the gain of the activation domain of ENL, or of other partner proteins, makes the fusion protein a constitutive trans-activator. This leads to constitutive over expression of MLL target genes that block stem cell commitment and promote stem cell renewal, probably the first step in MLL-related leukemogenesis.