title: The deficiency of tumor suppressor prep1 accelerates the onset of meis1- hoxa9 leukemogenesis.
abstract: Prep1 and Meis1 ortholog TALE transcription factors have opposing roles in tumorigenesis: Meis1 serves as an oncogene, Prep1 as a tumor suppressor. We now report that, Meis1 overexpression in primary Prep1-deficient (Prep1i/i) embryonic hematopoietic cells increases self-renewal potential of cells in vitro but not in vivo, whereas leukemia is instead obtained when Meis1 is combined with another oncogene, HoxA9. Prep1i/i Meis1-HoxA9-generated leukemic cells are less differentiated and grow more aggressively after the second passage in the mouse. These data indicate that Prep1 represents a barrier to the transforming activity of Meis1 in vitro, but its absence is not sufficient to induce early leukemogenesis. On the other hand, the Prep1i/i background appears to favor the insurgence of mutations that cause a more aggressive Meis1-HoxA9-generated leukemia. Indeed, the Prep1i/i leukemic cells upregulate the Polycomb protein Bmi-1 and expectedly down-regulate the Ink4a/Arf locus products. Finally, an important feature contributed by the Prep1i/i background is the post-transcriptional increase in Meis1 protein level.
authors.affiliation: Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), Milan, Italy.
authors.forename: Leila
authors.initials: L
authors.lastname: Dardaei
authors.affiliation: Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), Milan, Italy.
authors.forename: Livia
authors.initials: L
authors.lastname: Modica
authors.affiliation: Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), Milan, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Iotti
authors.affiliation: Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), Milan, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Blasi
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D005333:Fetus / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D007938:Leukemia / Q000473:pathology*; D008099:Liver / Q000473:pathology; D051379:Mice; D009154:Mutation; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D025521:Tumor Suppressor Proteins / Q000172:deficiency*
chemical_list: D018398:Homeodomain Proteins; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; C491412:Pknox1 protein, mouse; D025521:Tumor Suppressor Proteins