title: The clathrin-binding domain of CALM-AF10 alters the phenotype of myeloid neoplasms in mice.
abstract: The PICALM (CALM) gene, whose product is involved in clathrin-mediated endocytosis, has been identified in two recurring chromosomal translocations, involving either MLL or MLLT10 (AF10). We developed a mouse model of CALM-AF10(+) leukemia to examine the hypothesis that disruption of endocytosis contributes to leukemogenesis. Exclusion of the C-terminal portion of CALM from the fusion protein, which is required for optimal binding to clathrin, resulted in the development of a myeloproliferative disease, whereas inclusion of this domain led to the development of acute myeloid leukemia and changes in gene expression of several cancer-related genes, notably Pim1 and Crebbp. Nonetheless, the development of leukemia could not be attributed directly to interference with endocytosis or consequential changes in proliferation and signaling. In leukemia cells, full-length CALM-AF10 localized to the nucleus with no consistent effect on growth factor endocyctosis, and suppressed histone H3 lysine 79 methylation regardless of the presence of clathrin. Using fluorescence resonance energy transfer analysis, we show that CALM-AF10 has a propensity to homo-oligomerize, raising the possibility that the function of endocytic proteins involved in chimeric fusions may be to provide dimerization properties, a recognized mechanism for unleashing oncogenic properties of chimeric transcription factors, rather than disrupting the internalization of growth factor receptors.
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL 60637, USA. astoddar@bsd.uchicago.edu
authors.forename: A
authors.initials: A
authors.lastname: Stoddart
authors.forename: T R
authors.initials: TR
authors.lastname: Tennant
authors.forename: A A
authors.initials: AA
authors.lastname: Fernald
authors.forename: J
authors.initials: J
authors.lastname: Anastasi
authors.forename: F M
authors.initials: FM
authors.lastname: Brodsky
authors.forename: M M
authors.initials: MM
authors.lastname: Le Beau
mesh_terms: D000818:Animals; D002966:Clathrin / Q000502:physiology*; D004705:Endocytosis; D006657:Histones / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D015514:Oncogene Proteins, Fusion / Q000737:chemistry / Q000502:physiology*; D010641:Phenotype; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000378:metabolism
chemical_list: C114359:AF10-CALM fusion protein, human; D002966:Clathrin; D006657:Histones; D015514:Oncogene Proteins, Fusion; D017978:Receptors, Growth Factor; D019009:Proto-Oncogene Proteins c-kit