Apoptotic stimuli initiate MLL-AF9 translocations that are transcribed in cells capable of division.
Activation of apoptosis introduces a site-specific break within intron 11 of the MLL gene. Using the CD95 apoptotic signaling pathway in human lymphoblastoid cells, the 5' fragment of MLL undergoes translocation to intron 4 of AF9 and the proleukemogenic MLL-AF9 fusion gene created is transcribed. Both the breaks in MLL and transcription of the MLL-AF9 fusion gene are suppressed in the presence of the broad spectrum caspase inhibitor, zVAD.fmk. Duplicate cells containing sequence identical MLL-AF9 fusion junctions were identified within a cell population that had recovered from apoptosis. This indicated that cells harboring a translocation initiated by apoptotic cleavage had divided. These data are consistent with a novel pathogenic role for the apoptotic program where translocations with leukemogenic potential are created within cells that have the capacity to divide.
Betti
Christopher J
CJ
Program in Molecular Biology, Maywood, Illinois 60153, USA.
Villalobos
Michael J
MJ
Diaz
Manuel O
MO
Vaughan
Andrew T M
AT
D017209:Apoptosis / Q000235:genetics*; D002455:Cell Division / Q000235:genetics; D002460:Cell Line; D019457:Chromosome Breakage; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007438:Introns; D008214:Lymphocytes / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D051788:Myeloid-Lymphoid Leukemia Protein; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis / Q000235:genetics; D016133:Polymerase Chain Reaction / Q000379:methods; D011519:Proto-Oncogenes; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors; D014158:Transcription, Genetic; D014178:Translocation, Genetic; D019014:fas Receptor / Q000502:physiology
D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; C489901:MLLT3 protein, human; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors; D019014:fas Receptor; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase