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 determine whether CALM-AF10 and NES2-AF10 can induce leukemia in mice, we injected bone-marrow progenitor cells transduced with CALM-AF10 and NES2-AF10 into lethally irradiated mice. Seven out of eight mice transplanted with cells expressing CALM-AF10 developed leukemia within 6 months after transplantation (Fig.3a), and all mice transplanted with cells expressing NES2-AF10 developed leukemia within 3 months after transplantation. When cells prepared from bone marrow of these leukemic mice were transplanted into secondary recipient mice, all recipients promptly developed leukemia (medians: CALM-AF10 donors, 21 days [n = 4]; NES2-AF10 donors, 25 days [n = 9]). Morphological analysis revealed large populations of blast cells in leukemic mice receiving cells transduced with either CALM-AF10 or NES2-AF10 (Fig.3b,c). Flow cytometry analysis showed that cells expressing CALM-AF10 and NES2-AF10 in the bone marrow cells of primary recipient mice were Mac1+, CSF1R+ and c-kit+ (Fig.4a). Moreover, as shown in Figure4b, Hoxa5, Hoxa7, Hoxa9, Hoxa10 and Meis1 expression levels were upregulated in cells expressing CALM-AF10 and NES2-AF10 compared with normal bone marrow cells, although upregulation of Hoxa5 and Meis1 in primary recipient mice harboring NES2-AF10 was not significant (P = 0.084 and P = 0.093, respectively). These data demonstrate that the NES within CALM-AF10 is a critical element for induction of leukemia.
Affiliation: Division of Hematological Malignancy, National Cancer Center Research Institute, Tokyo, Japan.