Human Genetics

, Volume 119, Issue 5, pp 479–495 | Cite as

Common chromatin structures at breakpoint cluster regions may lead to chromosomal translocations found in chronic and acute leukemias

  • Reiner Strick
  • Yanming Zhang
  • Neelmini Emmanuel
  • Pamela L. Strissel
Original Investigation
First Online:
Received:
Accepted:

Abstract

The t(9;22) BCR/ABL fusion is associated with over 90% of chronic myelogenous and 25% of acute lymphocytic leukemia. Chromosome 11q23 translocations in acute myeloid and lymphoid leukemia cells demonstrate myeloid lymphoid leukemia (MLL) fusions with over 40 gene partners, like AF9 and AF4 on chromosomes 9 and 4, respectively. Therapy-related leukemia is associated with the above gene rearrangements following the treatment with topoisomerase II (topo II) inhibitors. BCR, ABL, MLL, AF9 and AF4 have defined patient breakpoint cluster regions. Chromatin structural elements including topo II and DNase I cleavage sites and scaffold attachment sites have previously been shown to closely associate with the MLL and AF9 breakpoint cluster regions, implicating these elements in non-homologous recombination (NHR). In this report, using cell lines and primary cells, chromatin structural elements were analyzed in BCR, ABL and AF4 and, for comparison, in MLL2, which is a homolog to MLL, but not associated with chromosome translocations. Topo II and DNase I cleavage sites associated with all breakpoint cluster regions, whereas SARs associated with ABL and AF4, but not with BCR. No close breakpoint clustering with the topo II/DNase I sites were observed; however, a statistically significant 5′ or 3′ distribution of patient breakpoints to the topo II DNase I sites was found, implicating DNA repair and exonucleases. Although MLL2 was expressed in all cell lines tested, except for the presence of one DNAse I site in the promoter, no other structural elements were found in MLL2. A NHR model presented demonstrates the importance of chromatin structure in chromosome translocations involved with leukemia.

Keywords

Acute Lymphocytic Leukemia Topo Chronic Myelogenous Leukemia Chromosome Translocation BV173 Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
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Notes

Acknowledgements

The authors would like to dedicate this study to Dr. Hewson Swift, from the University of Chicago, deceased in 2004, who supported the idea that “chromatin matters” in chromosomal rearrangements. The authors would also like to thank Dr. Janet Rowley for her continued support with this study. This project was supported by ACS Grant # 01-06 to PLS and RS

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Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Reiner Strick
    • 1
    • 2
  • Yanming Zhang
    • 1
  • Neelmini Emmanuel
    • 1
  • Pamela L. Strissel
    • 1
    • 2
  1. 1.Section of Hematology/Oncology, Department of MedicineUniversity of ChicagoChicagoUSA
  2. 2.Department of Obstetrics and GynecologyUniversity of Erlangen-Nuremberg, Laboratory for Molecular Medicine ErlangenGermany

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