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[Cancer Research 63, 1377-1381, March 15, 2003]
© 2003 American Association for Cancer Research

Molecular Biology and Genetics

Apoptotic Stimuli Initiate MLL-AF9 Translocations that Are Transcribed in Cells Capable of Division1

Christopher J. Betti, Michael J. Villalobos, Manuel O. Diaz and Andrew T. M. Vaughan2

Program in Molecular Biology [C. J. B., M. J. V.] and Departments of Radiation Oncology [A. T. M. V.] and Medicine [M. O. D.], Maywood, Illinois 60153

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.




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