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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Antibodies
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Blotting, Western
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COS Cells / metabolism
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Cell Differentiation / drug effects
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Cell Division / drug effects
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Cell Division / genetics
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Cell Line / drug effects
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Cell Nucleus / genetics
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Cell Nucleus / metabolism
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Chromosomes, Human, Pair 11
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / immunology
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Fluorescent Antibody Technique, Indirect
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Granulocyte Colony-Stimulating Factor / pharmacology
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Hematopoietic Stem Cells / drug effects
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Hematopoietic Stem Cells / pathology
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Histone-Lysine N-Methyltransferase
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Humans
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Leukemia / genetics*
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Leukemia / pathology
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Mice
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Molecular Sequence Data
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Myeloid-Lymphoid Leukemia Protein
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Neoplasm Proteins / immunology
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Nuclear Proteins*
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Proto-Oncogenes*
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Rabbits
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Recombinant Proteins / biosynthesis
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Recombinant Proteins / genetics
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Staining and Labeling / methods
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Transcription Factors*
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Translocation, Genetic*
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Tumor Cells, Cultured
Substances
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Antibodies
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DNA-Binding Proteins
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KMT2A protein, human
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MLLT3 protein, human
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Mllt3 protein, mouse
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Neoplasm Proteins
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Nuclear Proteins
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Recombinant Proteins
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Transcription Factors
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Granulocyte Colony-Stimulating Factor
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Myeloid-Lymphoid Leukemia Protein
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Histone-Lysine N-Methyltransferase
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Kmt2a protein, mouse