The elongation domain of ELL is dispensable but its ELL-Associated factor 1 interaction domain is essential for MLL-ELL-induced leukemogenesis
The elongation domain of ELL is dispensable but its ELL-Associated factor 1 interaction domain is essential for MLL-ELL-induced leukemogenesis
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DOI：
10.1128/mcb.21.16.5678-5687.2001
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发表时间：
2001-08-01
影响因子：
5.3
通讯作者：
Thirman, MJ
中科院分区：
文献类型：
--
作者：
Luo, RT;Lavau, C;Thirman, MJ
MLL-ELL嵌合基因是与新发和治疗相关的急性髓性白血病（AML）相关的（11;19）（q23p13.1）易位的产物。ELL是一种RNA聚合酶II延伸因子，与最近鉴定的EAF 1（ELL相关因子1）蛋白相互作用。EAF 1包含与白血病中融合至MLL的其他三个基因AF 4、LAF 4和AF 5 q31的转录激活结构域的有限同源区域。使用逆转录病毒转导的髓系祖细胞的体外转化试验，我们进行了MLL-ELL的结构-功能分析。而ELL的延伸结构域是EAF 1的，EAF 1相互作用结构域是MLL-ELL体外永生化特性的关键。为了在体内证实这些结果，我们将MLL与ELL的最小EAF 1相互作用结构域融合的骨髓转导小鼠移植。这些小鼠都发生了AML，潜伏期比移植野生型MLL-ELL融合体的小鼠更长。基于这些结果，我们构建了一个异源MLL-EAF 1融合基因，并分析了其转化潜力。引人注目的是，我们发现MLL-EAF 1以与MLL-ELL相同的方式使骨髓祖细胞永生化。此外，移植用MLL-EAF 1转导的骨髓诱导AML的潜伏期比移植MLL-ELL融合体的小鼠短。总之，这些结果表明，白血病活性的MLL-ELL需要EAF 1相互作用域的ELL，这表明，由MLL的反式激活结构域的招聘类似于在EAF 1或AF 4/LAF 4/AF 5 q31家庭可能是一个重要的共同特点，多个11 q23易位。此外，这些研究支持MLL伴侣基因及其蛋白质-蛋白质相互作用在11 q23白血病发生中的关键作用。
The MLL-ELL chimeric gene is the product of the (11;19)(q23p13.1) translocation associated with de novo and therapy-related acute myeloid leukemias (AML). ELL is an RNA polymerase II elongation factor that interacts with the recently identified EAF1 (ELL associated factor 1) protein. EAF1 contains a limited region of homology with the transcriptional activation domains of three other genes fused to MLL in leukemias, AF4, LAF4, and AF5q31. Using an in vitro transformation assay of retrovirally transduced myeloid progenitors, we conducted a structure-function analysis of MLL-ELL. Whereas the elongation domain of ELL was dispensable, the EAF1 interaction domain of ELL was critical to the immortalizing properties of MLL-ELL in vitro. To confirm these results in vivo, we transplanted mice with bone marrow transduced with MLL fused to the minimal EAF1 interaction domain of ELL. These mice all developed AML, with a longer latency than mice transplanted with the wild-type MLL-ELL fusion. Based on these results, we generated a heterologous MLL-EAF1 fusion gene and analyzed its transforming potential. Strikingly, we found that MLL-EAF1 immortalized myeloid progenitors in the same manner as that of MLL-ELL. Furthermore, transplantation of bone marrow transduced with MLL-EAF1 induced AML with a shorter latency than mice transplanted with the MLL-ELL fusion. Taken together, these results indicate that the leukemic activity of MLL-ELL requires the EAF1 interaction domain of ELL, suggesting that the recruitment by MLL of a transactivation domain similar to that in EAF1 or the AF4/LAF4/AF5q31 family may be a critical common feature of multiple 11q23 translocations. In addition, these studies support a critical role for MLL partner genes and their protein-protein interactions in 11q23 leukemogenesis.