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Rearrangements of the MLL gene are influenced by DNA secondary structure, potentially mediated by topoisomerase II binding
Author(s) -
Le Hongan,
Singh Sheetal,
Shih ShyhJen,
Du Nga,
Schnyder Sabine,
Loredo Grace A.,
Bien Christine,
Michaelis Laura,
Toor Amir,
Diaz Manuel O.,
Vaughan Andrew T.
Publication year - 2009
Publication title -
genes, chromosomes and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.754
H-Index - 119
eISSN - 1098-2264
pISSN - 1045-2257
DOI - 10.1002/gcc.20685
Subject(s) - breakpoint , biology , chromosomal translocation , microbiology and biotechnology , topoisomerase , exon , recombination signal sequences , genetics , gene , dna , recombination , recombination activating gene
Abstract 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. © 2009 Wiley‐Liss, Inc.