title: Identification of MLL and chimeric MLL gene products involved in 11q23 translocation and possible mechanisms of leukemogenesis by MLL truncation.
abstract: 11q23 chromosome aberrations are frequently observed in infantile as well as therapy-related leukemias. The target gene at 11q23, MLL, is disrupted by the translocation and becomes fused to various translocation partner genes such as AF4/FEL, LTG9/AF9 and LTG19/ENL. The resulting chimeric mRNAs are fused in frame and have been predicted to encode leukemia-specific chimeric proteins. In the present study, we raised antibodies against MLL, LTG9 and LTG19 and demonstrated that MLL and chimeric MLL-LTG9 and MLL-LTG19 products are synthesized in vivo and are localized in the nuclei, using immunofluorescence and cell fractionation studies. The truncated N-terminal portion of the MLL product common to the various types of 11q23 translocation was also localized in the nuclei in a similar fashion. Murine 32Dc13 cells stably expressing the truncated N-terminal MLL protein exhibited an inhibition of differentiation and a growth advantage following stimulation by granulocyte-colony stimulating factor, although the IL-3 dependency was not significantly changed in comparison to the parental cells. These results suggest that the N-terminal portion common to various MLL-chimeric products plays an important role in leukemogenesis.
authors.affiliation: Laboratory of Chemotherapy, Aichi Cancer Center Research Institute, Nagoya, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Joh
authors.forename: Y
authors.initials: Y
authors.lastname: Kagami
authors.forename: K
authors.initials: K
authors.lastname: Yamamoto
authors.forename: T
authors.initials: T
authors.lastname: Segawa
authors.forename: J
authors.initials: J
authors.lastname: Takizawa
authors.forename: T
authors.initials: T
authors.lastname: Takahashi
authors.forename: R
authors.initials: R
authors.lastname: Ueda
authors.forename: M
authors.initials: M
authors.lastname: Seto
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000906:Antibodies; D015153:Blotting, Western; D019556:COS Cells / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects / Q000235:genetics; D002460:Cell Line / Q000187:drug effects; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D002880:Chromosomes, Human, Pair 11; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D019084:Fluorescent Antibody Technique, Indirect; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D051788:Myeloid-Lymphoid Leukemia Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D009687:Nuclear Proteins; D011519:Proto-Oncogenes; D011817:Rabbits; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics; D013194:Staining and Labeling / Q000379:methods; D014157:Transcription Factors; D014178:Translocation, Genetic; D014407:Tumor Cells, Cultured
chemical_list: D000906:Antibodies; D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; C489901:MLLT3 protein, human; C489902:Mllt3 protein, mouse; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011994:Recombinant Proteins; D014157:Transcription Factors; D016179:Granulocyte Colony-Stimulating Factor; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse