The clathrin-binding domain of CALM and the OM-LZ domain of AF10 are sufficient to induce acute myeloid leukemia in mice

被引：28
作者：
Deshpande, A. J. [1 ,2 ,3 ]
Rouhi, A. [4 ]
Lin, Y. [5 ]
Stadler, C. [1 ,2 ]
Greif, P. A. [1 ,2 ]
Arseni, N. [1 ,2 ]
Opatz, S. [1 ,2 ]
Quintanilla-Fend, L. [6 ]
Holzmann, K. [7 ]
Hiddemann, W. [1 ,2 ]
Doehner, K. [8 ]
Doehner, H. [8 ]
Xu, G. [5 ]
Armstrong, S. A. [3 ]
Bohlander, S. K. [1 ,2 ]
Buske, C. [4 ]
机构：
[1] Univ Munich, Klinikum Grosshadern, Dept Med 3, D-8000 Munich, Germany
[2] Helmholtz Ctr Environm Hlth, Clin Cooperat Grp Leukemia, Munich, Germany
[3] Harvard Univ, Childrens Hosp, Sch Med, Div Hematol Oncol, Boston, MA 02115 USA
[4] Univ Hosp Ulm, Inst Expt Canc Res, Ctr Comprehens Canc, D-89081 Ulm, Germany
[5] Chinese Acad Sci, State Key Lab Mol Biol, Inst Biochem & Cell Biol, Shanghai, Peoples R China
[6] Univ Tubingen, Inst Pathol, D-7400 Tubingen, Germany
[7] Univ Hosp Ulm, Chip Facil ZKF, D-89081 Ulm, Germany
[8] Univ Hosp Ulm, Dept Internal Med 3, D-89081 Ulm, Germany
来源：
LEUKEMIA | 2011年 / 25卷 / 11期
基金：
加拿大健康研究院; 美国国家科学基金会;
关键词：
CALM; AF10; acute myeloid leukemia; ACUTE LYMPHOBLASTIC-LEUKEMIA; CALM/AF10; FUSION; LEUCINE-ZIPPER; SUBCELLULAR-LOCALIZATION; MLL-MLLT10; STEM-CELL; CALM-AF10; PROTEIN; MLL; GENE;
D O I：
10.1038/leu.2011.153
中图分类号：
R73 [肿瘤学];
学科分类号：
100214 ;
摘要：
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
引用
收藏
页码：1718 / 1727
页数：10
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