Nuclear export signal within CALM is necessary for CALM-AF10-induced leukemia
Article first published online: 13 FEB 2014
© 2014 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
Volume 105, Issue 3, pages 315–323, March 2014
How to Cite
Cancer Sci 105 (2014) 315–323
- Issue published online: 6 MAR 2014
- Article first published online: 13 FEB 2014
- Accepted manuscript online: 8 JAN 2014 01:44AM EST
- Manuscript Accepted: 30 DEC 2013
- Manuscript Revised: 5 DEC 2013
- Manuscript Received: 16 SEP 2013
- Ministry of Health, Labor, and Welfare
- Ministry of Education, Culture, Sports, Science, and Technology
- National Cancer Center Research and Development Fund
- Naito Foundation
- Cosmetology Research Foundation
- Nara Women's University Intramural Grant for Project Research
- chromosome translocation;
- histone modification;
- nuclear export signal
The CALM–AF10 fusion gene, which results from a t(10;11) translocation, is found in a variety of hematopoietic malignancies. Certain HOXA cluster genes and MEIS1 genes are upregulated in patients and mouse models that express CALM-AF10. Wild-type clathrin assembly lymphoid myeloid leukemia protein (CALM) primarily localizes in a diffuse pattern within the cytoplasm, whereas AF10 localizes in the nucleus; however, it is not clear where CALM-AF10 acts to induce leukemia. To investigate the influence of localization on leukemogenesis involving CALM-AF10, we determined the nuclear export signal (NES) within CALM that is necessary and sufficient for cytoplasmic localization of CALM-AF10. Mutations in the NES eliminated the capacity of CALM-AF10 to immortalize murine bone-marrow cells in vitro and to promote development of acute myeloid leukemia in mouse models. Furthermore, a fusion of AF10 with the minimal NES can immortalize bone-marrow cells and induce leukemia in mice. These results suggest that during leukemogenesis, CALM-AF10 plays its critical roles in the cytoplasm.