Rearrangements of the MLL gene are influenced by DNA secondary structure, potentially mediated by topoisomerase II binding. Genes Chromosomes Cancer 2009 Sep;48(9):806-15
Date
06/17/2009Pubmed ID
19530238Pubmed Central ID
PMC2764312DOI
10.1002/gcc.20685Scopus ID
2-s2.0-68549135307 (requires institutional sign-in at Scopus site) 33 CitationsAbstract
The location of MLL translocation breakpoints within therapy-related acute myeloid leukemia linked to drugs targeting Topoisomerase II and infant acute leukemia (IAL) are biased toward the intron 11-exon 12 region of MLL, although lacking a comprehensive explanation. To address this, blood samples were taken from breast cancer and lymphoma patients receiving Topoisomerase II inhibitor therapy. Inverse PCR analysis was used to interrogate the exon 12 region of MLL for rearrangements. Eleven of 19 observed translocations showed breakpoint junctions restricted to a single 5 bp location within exon 12. A similarly restricted distribution (11/20 breakpoint junctions) was observed in TK6 cells exposed to either estrogen (linked to IAL) or anti-CD95 antibody. The translocation hotspot was at the 5' edge of a 10-bp tract matched with a perfect palindrome, 101 bp distant. A high stringency Topoisomerase II consensus sequence binding site was noted at the geometric midpoint of the palindromes. Ligation-mediated PCR to screen TK6 cells exposed to anti-CD95 antibody showed 14/37 (38%) of DNA breaks adjacent to the 5' palindrome and 10/37 (27%) at the 3' partner. We propose a model whereby Topoisomerase II facilitates the organization of nuclease-sensitive secondary structures, stabilized by palindrome association, which are prone to rearrangement.
Author List
Le H, Singh S, Shih SJ, Du N, Schnyder S, Loredo GA, Bien C, Michaelis L, Toor A, Diaz MO, Vaughan ATAuthor
Laura Michaelis MD Chief, Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AdultAged
Base Sequence
Breast Neoplasms
Cell Line
DNA
DNA Topoisomerases, Type II
Female
Gene Rearrangement
Histone-Lysine N-Methyltransferase
Humans
Inverted Repeat Sequences
Lymphoma
Male
Middle Aged
Molecular Sequence Data
Myeloid-Lymphoid Leukemia Protein
Neoplasms, Second Primary
Nucleic Acid Conformation
Topoisomerase II Inhibitors
Translocation, Genetic
