The clathrin-binding domain of CALM and the OM-LZ domain of AF10 are sufficient to induce acute myeloid leukemia in mice
The clathrin-binding domain of CALM and the OM-LZ domain of AF10 are sufficient to induce acute myeloid leukemia in mice
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DOI：
10.1038/leu.2011.153
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发表时间：
2011-11-01
期刊：
影响因子：
11.4
通讯作者：
Buske, C.
中科院分区：
文献类型：
--
作者：
Deshpande, A. J.;Rouhi, A.;Buske, C.
t（10; 11）（p13-14;q14-21）易位，引起CALM-AF 10融合基因，是在预后不良的急性髓性白血病（AML）患者中观察到的复发性染色体重排。尽管在AML患者中已经描述了CALM-AF 10融合转录物的剪接，但不同的CALM和AF 10结构域对体内白血病发生的贡献仍有待确定。因此，我们进行了详细的结构-功能研究的CALM-AF 10融合蛋白。我们证明，融合的C-末端248个氨基酸的CALM，其中包括网格蛋白结合结构域，八肽基序亮氨酸拉链（OM-LZ）结构域的AF 10产生的融合蛋白（称为CALM-AF 10最小融合（MF）），具有显着增强的转化能力，在菌落试验中，提供了一个有效的系统快速评估CALM-AF 10介导的转化。由CALM-AF 10（MF）突变体诱导的白血病重现了全长CALM-AF 10诱导的白血病的多个方面，包括异常Hoxa簇上调，这是CALM-AF 10白血病的特征性分子病变。总之，该研究表明，网格蛋白结合和CALM-AF 10的OM-LZ结构域的协作足以诱导AML。这些发现进一步表明，未来拮抗CALM-AF 10诱导的转化的方法应该包括旨在阻断这些关键结构域的策略。Leukemia（2011）25，1718-1727; doi：10.1038/leu.2011.153; 2011年6月17日在线发表
The t(10; 11)(p13-14;q14-21) translocation, giving rise to the CALM-AF10 fusion gene, is a recurrent chromosomal rearrangement observed in patients with poor prognosis acute myeloid leukemia (AML). Although splicing of the CALM-AF10 fusion transcripts has been described in AML patients, the contribution of different CALM and AF10 domains to in vivo leukemogenesis remains to be defined. We therefore performed detailed structure-function studies of the CALM-AF10 fusion protein. We demonstrate that fusion of the C-terminal 248 amino acids of CALM, which include the clathrin-binding domain, to the octapeptide motif-leucine-zipper (OM-LZ) domain of AF10 generated a fusion protein (termed CALM-AF10 minimal fusion (MF)), with strikingly enhanced transformation capabilities in colony assays, providing an efficient system for the expeditious assessment of CALM-AF10-mediated transformation. Leukemias induced by the CALM-AF10 (MF) mutant recapitulated multiple aspects of full-length CALM-AF10-induced leukemia, including aberrant Hoxa cluster upregulation, a characteristic molecular lesion of CALM-AF10 leukemias. In summary, this study indicates that collaboration of the clathrin-binding and the OM-LZ domains of CALM-AF10 is sufficient to induce AML. These findings further suggest that future approaches to antagonize CALM-AF10-induced transformation should incorporate strategies, which aim at blocking these key domains. Leukemia (2011) 25, 1718-1727; doi:10.1038/leu.2011.153; published online 17 June 2011