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: We next investigated whether the NES within CALM-AF10 is required for leukemogenesis. To this end, primary murine bone-marrow stem/progenitor cells (HSPC) were infected with retrovirus encoding CALM-AF10, CALMNES4A-AF10, NES2-AF10 and mAF10. Serial-replating assays revealed that both CALM-AF10 and NES2-AF10 immortalized HSPC, and that the cells formed colonies for at least five rounds of replating (Fig.2a). By contrast, neither mAF10 nor CALMNES4A-AF10, which lacks a functional CALM NES, could immortalize cells. Transduced cells with elevated colony-forming abilities also exhibited upregulation of the Hoxa cluster (Hoxa5, Hoxa7, Hoxa9 and Hoxa10) and Meis1 genes (Fig.2b)7,9. These results indicated that the CALM NES is necessary for CALM-AF10 to immortalize hematopoietic stem/progenitor cells.
Affiliation: Division of Hematological Malignancy, National Cancer Center Research Institute, Tokyo, Japan.