Molecular analysis of 13 cases of MLL/11q23 secondary acute leukemia and identification of topoisomerase II consensus-binding sequences near the chromosomal breakpoint of a secondary leukemia with the t(4;11).
Rearrangements of the MLL (Mixed Lineage Leukemia) gene in the human 11q23 cytogenetic locus have been detected in secondary (therapy-related) acute leukemias in patients who have received topoisomerase II inhibitors for prior, independent neoplasms. The topoisomerase II inhibitors implicated in MLL/11q23 secondary leukemias all inhibit the religation step of reaction catalyzed by topoisomerase II. This results in the stabilization of a 'cleavable complex' with double-strand DNA breaks at the point of topoisomerase II binding. This raises the possibility that the cleavable complex participates in the translocation process in MLL/11q23 secondary leukemias. Here we report that the MLL/11q23 breakpoints in 13/13 patients with secondary leukemia map to the same breakpoint cluster region (bcr) noted in de novo MLL/11q23 acute leukemias and the presence of in vivo topoisomerase II inhibitor-induced cleavage sites in MLL/11q23 bcr. We have also cloned and sequenced the breakpoint from a MLL/11q23 secondary acute leukemia. This analysis revealed sequences similar to the consensus sequence for vertebrate topoisomerase II binding and cleavage close to the 11q23 and 4q21 breakpoints. These results support a role for topoisomerase II in mechanism generating translocations in MLL/11q23 secondary acute leukemia.
Domer
P H
PH
Department of Pathology, Northwestern University Medical School, Chicago, IL 60611, USA.
Head
D R
DR
Renganathan
N
N
Raimondi
S C
SC
Yang
E
E
Atlas
M
M
D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D001665:Binding Sites; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations / Q000235:genetics*; D025063:Chromosome Disorders; D002880:Chromosomes, Human, Pair 11; D002894:Chromosomes, Human, Pair 4; D003001:Cloning, Molecular; D016384:Consensus Sequence; D017931:DNA Primers / Q000737:chemistry; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000473:pathology*; D008297:Male; D008969:Molecular Sequence Data; D051788:Myeloid-Lymphoid Leukemia Protein; D012150:Polymorphism, Restriction Fragment Length; D011519:Proto-Oncogenes; D015183:Restriction Mapping; D014157:Transcription Factors; D014178:Translocation, Genetic
D017931:DNA Primers; D004268:DNA-Binding Proteins; C497422:KMT2A protein, human; D014157:Transcription Factors; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; D004250:DNA Topoisomerases, Type II