Journal
LEUKEMIA
Volume 25, Issue 11, Pages 1718-1727Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/leu.2011.153
Keywords
CALM; AF10; acute myeloid leukemia
Categories
Funding
- Deutsche Krebshilfe [10-1838-Bu 2]
- Deutsche Forschungsgemeinschaft DFG [SFB 684, A6]
- German Ministry of Education and Research (BMBF) National Genome Research Network (NGFNplus) [PKL-01GS0876-6]
- Canadian Institutes of Health Research (CIHR)
- Baustein Startforderung at University Hospital Ulm
- Deutsche Jose-Carreras-Leukamie-Stiftung [F05/06]
- Ministry of Science and Technology of China [2005CB522400, 2006CB943900, KSCX2-YWN-019]
- Max-Planck-Gesellschaft of Germany
- National Science Foundation of China
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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
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