Surviving apoptosis: a possible mechanism of benzene-induced leukemia.
The pathological consequences resulting from deregulation of the apoptotic program include cancer (too little apoptosis) or diseases of cell deprivation, such as Alzheimer's (too much apoptosis). We have identified an additional pathology whereby cells reaching the earliest stage of chromatin cleavage have the potential to suppress apoptotic execution and survive. One specific cleavage event associated with this process is restricted to a location within the mixed lineage leukemia (MLL) gene at 11q23. The site of cleavage is consistent with the location where large, approximately 50 kbp loops of supercoiled DNA are attached to the nuclear matrix. Cells modified by this process generate MLL translocations, as shown by inverse PCR, that survive for days to weeks but which have no known relationship with clinical disease. Using a specific approach, cells stimulated by anti-CD95 antibody, a potent stimulator of the apoptotic program, facilitated creation of the MLL-AF9 fusion gene. Further, this rearrangement, which is commonly observed in patients with AML linked to exposure to cytotoxic agents, was efficiently transcribed in cells that were able to undergo cell division. These data are discussed in the context of benzene and benzene metabolite toxicity that impacts the process of apoptosis and is known to lead to leukemic disease.
Vaughan
Andrew T
AT
Department of Radiation Oncology, University of California, Davis, 4501 X Street, Suite G 126, Sacramento, CA 95817, USA. andrew.vaughn@ucdmc.ucdavis.edu
Betti
Christopher J
CJ
Villalobos
Michael J
MJ
Premkumar
Kumpati
K
Cline
Edith
E
Jiang
Qun
Q
Diaz
Manuel O
MO
D000818:Animals; D017209:Apoptosis; D001554:Benzene / Q000633:toxicity*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007938:Leukemia / Q000139:chemically induced*; D008954:Models, Biological; D051788:Myeloid-Lymphoid Leukemia Protein; D011519:Proto-Oncogenes / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; D001554:Benzene