Effects of topoisomerase 2 inhibitors on the MLL gene in children receiving chemotherapy: a prospective study.
The molecular effects of etoposide in haemopoietic cells suggest that mixed lineage leukaemia (MLL) abnormalities can be biomarkers of patient susceptibility to the genotoxic effects of topoisomerase 2 (topo 2) inhibitors. We have prospectively studied treatment-related MLL cleavage and rearrangement in serial samples from 71 children receiving chemotherapy, using Southern blot analysis and panhandle PCR. The results were related to patient demographics, treatment details and outcome. MLL cleavage was identified in six bone marrow samples from five patients 2-10 months after the start of therapy. There was no obvious relationship between the degree of MLL cleavage and cumulative dose or schedule of topo 2 inhibitors. Three children with low percentage (23-30%) cleavage remained well and two were still receiving treatment at study completion. One child with two consecutively positive samples and higher level of MLL cleavage (45-48%) died from treatment-related toxicities and relapsed leukaemia. A patient with haemophagocytic lymphohistiocytosis developed the highest level of MLL cleavage (50%) at 3 months and a treatment-related leukaemia with MLL rearrangement 6 months after the start of treatment. It would appear that some patients are inherently more susceptible to the genotoxic effect of topo 2 inhibitors. The degree and persistence of MLL cleavage may identify patients at risk.
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Immunogenetics Laboratory, University of Manchester and Central Manchester and Manchester Children's University Hospital Trust, Manchester, UK.
Taylor
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Wynn
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Eden
O B
OB
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D015321:Gene Rearrangement; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007223:Infant; D007938:Leukemia / Q000188:drug therapy* / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D051788:Myeloid-Lymphoid Leukemia Protein; D011519:Proto-Oncogenes / Q000187:drug effects / Q000235:genetics*; D044469:Racial Groups; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics*; D016896:Treatment Outcome
D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; C497422:KMT2A protein, human; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; D004250:DNA Topoisomerases, Type II