title: Mapping of MN1 sequences necessary for myeloid transformation.
abstract: The MN1 oncogene is deregulated in human acute myeloid leukemia and its overexpression induces proliferation and represses myeloid differentiation of primitive human and mouse hematopoietic cells, leading to myeloid leukemia in mouse models. To delineate the sequences within MN1 necessary for MN1-induced leukemia, we tested the transforming capacity of in-frame deletion mutants, using retroviral transduction of mouse bone marrow. We found that integrity of the regions between amino acids 12 to 458 and 1119 to 1273 are required for MN1's in vivo transforming activity, generating myeloid leukemia with some mutants also producing T-cell lympho-leukemia and megakaryocytic leukemia. Although both full length MN1 and a mutant that lacks the residues between 12-228 (Δ12-228 mutant) repressed myeloid differentiation and increased myeloproliferative activity in vitro, the mutant lost its transforming activity in vivo. Both MN1 and Δ12-228 increased the frequency of common myeloid progentiors (CMP) in vitro and microarray comparisons of purified MN1-CMP and Δ12-228-CMP cells showed many differentially expressed genes including Hoxa9, Meis1, Myb, Runx2, Cebpa, Cebpb and Cebpd. This collection of immediate MN1-responsive candidate genes distinguishes the leukemic activity from the in vitro myeloproliferative capacity of this oncoprotein.
authors.affiliation: Department of Genetics, St Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
authors.forename: Ayten
authors.initials: A
authors.lastname: Kandilci
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Surtel
authors.forename: Laura
authors.initials: L
authors.lastname: Janke
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Neale
authors.forename: Sabrina
authors.initials: S
authors.lastname: Terranova
authors.forename: Gerard C
authors.initials: GC
authors.lastname: Grosveld
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D002452:Cell Count; D002454:Cell Differentiation; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005822:Genetic Vectors; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D022423:Myeloid Cells / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D017384:Sequence Deletion; D016019:Survival Analysis; D015534:Trans-Activators; D014161:Transduction, Genetic; D025521:Tumor Suppressor Proteins
chemical_list: C501081:Mn1 protein, mouse; D009363:Neoplasm Proteins; D015513:Oncogene Proteins; D015534:Trans-Activators; D025521:Tumor Suppressor Proteins