Identification of MLL and chimeric MLL gene products involved in 11q23 translocation and possible mechanisms of leukemogenesis by MLL truncation.
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.
Joh
T
T
Laboratory of Chemotherapy, Aichi Cancer Center Research Institute, Nagoya, Japan.
Kagami
Y
Y
Yamamoto
K
K
Segawa
T
T
Takizawa
J
J
Takahashi
T
T
Ueda
R
R
Seto
M
M
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
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