title: Nuclear export signal within CALM is necessary for CALM-AF10-induced leukemia.
abstract: 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.
authors.affiliation: Division of Hematological Malignancy, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Mai
authors.initials: M
authors.lastname: Suzuki
authors.forename: Kazutsune
authors.initials: K
authors.lastname: Yamagata
authors.forename: Mika
authors.initials: M
authors.lastname: Shino
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Aikawa
authors.forename: Koichi
authors.initials: K
authors.lastname: Akashi
authors.forename: Toshio
authors.initials: T
authors.lastname: Watanabe
authors.forename: Issay
authors.initials: I
authors.lastname: Kitabayashi
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism; D002522:Chlorocebus aethiops; D005260:Female; D007938:Leukemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D034041:Monomeric Clathrin Assembly Proteins / Q000737:chemistry / Q000502:physiology*; D009368:Neoplasm Transplantation; D049790:Nuclear Export Signals; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: C490477:Mllt10 protein, mouse; D034041:Monomeric Clathrin Assembly Proteins; D049790:Nuclear Export Signals; D015514:Oncogene Proteins, Fusion; C573094:PICALM protein, mouse; D014157:Transcription Factors
keywords: AF10; chromosome translocation; histone modification; leukemia; nuclear export signal