Nuclear export signal within CALM is necessary for CALM-AF10-induced leukemia.
Bottom Line: The CALM-AF10 fusion gene, which results from a t(10;11) translocation, is found in a variety of hematopoietic malignancies.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.These results suggest that during leukemogenesis, CALM-AF10 plays its critical roles in the cytoplasm.
Affiliation: Division of Hematological Malignancy, National Cancer Center Research Institute, Tokyo, Japan.Show MeSH
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Mentions: To investigate the role of subcellular localization of CALM-AF10 in leukemogenesis, we focused on the NES within the CALM portion of the fusion protein (amino acids 543–554 of CALM).9 We generated NES-deficient mutants CALMNES4A-AF10 and CALMNES4A, in which leucine-544, leucine-547, leucine-551 and isoleucine-553 in the putative NES region within CALM were substituted with alanines (NES4A) (Fig.1a). Expression vectors for FLAG-tagged CALM-AF10, CALM, CALMNES4A-AF10, CALMNES4A and mAF10 (the AF10 portion of CALM-AF10) were transiently transfected into COS-7 cells. Immunofluorescence analysis revealed that CALM and CALM-AF10 primarily localized in the cytoplasm, whereas mAF10 and the NES mutants CALMNES4A-AF10 and CALMNES4A localized in the nucleus (Fig.1b,c).
Affiliation: Division of Hematological Malignancy, National Cancer Center Research Institute, Tokyo, Japan.