The clathrin-binding domain of CALM and the OM-LZ domain of AF10 are sufficient to induce acute myeloid leukemia in mice
Copyright policy )The clathrin-binding domain of CALM and the OM-LZ domain of AF10 are sufficient to induce acute myeloid leukemia in mice
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.
- Chinese Academy of Sciences China (People's Republic of)
- Medical Research Council United Kingdom
- Pathologisches Institut Germany
- State Key Laboratory of Molecular Biology China (People's Republic of)
- University of Ulm Germany
Mice, Inbred C3H, Gene Expression Profiling, Blotting, Western, Clathrin, Mice, Inbred C57BL, Leukemia, Myeloid, Acute, Mice, Microscopy, Fluorescence, CALM; AF10; acute myeloid leukemia, Monomeric Clathrin Assembly Proteins, Animals, Humans, Cells, Cultured, Transcription Factors
Mice, Inbred C3H, Gene Expression Profiling, Blotting, Western, Clathrin, Mice, Inbred C57BL, Leukemia, Myeloid, Acute, Mice, Microscopy, Fluorescence, CALM; AF10; acute myeloid leukemia, Monomeric Clathrin Assembly Proteins, Animals, Humans, Cells, Cultured, Transcription Factors
citations This is an alternative to the "Influence" indicator, which also reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).29 popularity This indicator reflects the "current" impact/attention (the "hype") of an article in the research community at large, based on the underlying citation network.Top 10% influence This indicator reflects the overall/total impact of an article in the research community at large, based on the underlying citation network (diachronically).Top 10% impulse This indicator reflects the initial momentum of an article directly after its publication, based on the underlying citation network.Top 10%
Citations provided by BIP!Popularity provided by BIP!