Mapping of MN1 sequences necessary for myeloid transformation

• Published in: PloS one Vol. 8; no. 4; p. e61706
• Main Authors: Kandilci, Ayten, Surtel, Jacqueline, Janke, Laura, Neale, Geoffrey, Terranova, Sabrina, Grosveld, Gerard C
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 23.04.2013; Public Library of Science (PLoS)
• Subjects: Acute myeloid leukemia; Amino Acid Sequence; Amino acids; Animal models; Animals; Bioinformatics; Biology; Bone marrow; Bone Marrow Cells - metabolism; Bone Marrow Cells - pathology; Cbfa-1 protein; Cell Count; Cell Differentiation; Cell Proliferation; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cell Transformation, Neoplastic - pathology; Clonal deletion; Deletion mutant; Deregulation; Differentiation; Enzymes; Gene deletion; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genes; Genetic transformation; Genetic Vectors; Genetics; Hemorrhagic thrombocythemia; Humans; Laboratory animals; Leukemia; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - mortality; Leukemia, Myeloid, Acute - pathology; Lymphocytes T; Medical prognosis; Medicine; Mice; Molecular biology; Molecular Sequence Data; Mutants; Myeloid Cells - metabolism; Myeloid Cells - pathology; Myeloid leukemia; Neoplasm Proteins - genetics; Neoplasm Proteins - metabolism; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Oncogene Proteins - genetics; Oncogene Proteins - metabolism; Proteins; Retroviridae - genetics; Sequence Deletion; Stem cell transplantation; Survival Analysis; Trans-Activators; Transcription factors; Transduction, Genetic; Transformation; Tumor Suppressor Proteins; United States > US; Tennessee
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0061706

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.