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Blood, 1 March 2005, Vol. 105, No. 5, pp. 2124-2131. Prepublished online as a Blood First Edition Paper on November 4, 2004; DOI 10.1182/blood-2004-07-2683. This Article Full Text (PDF) All Versions of this Article: 2004-07-2683v1 105/5/2124    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Libura, J. Articles by Richardson, C. Search for Related Content PubMed PubMed Citation Articles by Libura, J. Articles by Richardson, C. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 16, 2004 Accepted October 27, 2004 t-AML-like MLL rearrangements are induced by etoposide in primary human CD34+ cells and remain stable after clonal expansion Jolanta Libura, Diana J Slater, Carolyn A Felix, and Christine Richardson* Institute of Cancer Genetics, Department of Pathology, Columbia University College of Physicians and Surgeons, New York, NY, USA Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA * Corresponding author; email: car10{at}columbia.edu. Rearrangements involving the MLL gene on chromosome band 11q23 are a hallmark of therapy-related acute myeloid leukemias following treatment with topoisomeraseII poisons including etoposide. Therapy-related and de novo genomic translocation breakpoints cluster within a well-characterized 8.3kb fragment of MLL. Repair of etoposide-stabilized DNA topoisomeraseII covalent complexes may initiate MLL rearrangements observed in patients. We used a culture system of primary human hematopoietic CD34+ cells and inverse PCR to characterize the spectrum of stable genomic rearrangements promoted by etoposide exposure originating within an MLL translocation hotspot in therapy-related leukemia. Alterations to the region were observed at a readily detectable frequency in etoposide-treated cells. Illegitimate repair events after minimal repair included MLL tandem duplications and translocations, with minor populations of deletions or insertions. In stably repaired cells that proliferated for 10-14 days, the significant majority of illegitimate events were MLL tandem duplications, and several deletions, inversions, insertions, and translocations. Thus, etoposide promotes specific rearrangements of MLL consistent with the full spectrum of oncogenic events identified in leukemic samples. Although etoposide-initiated rearrangements are frequent, only a small subset of translocations occurs in cells that proliferate significantly. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: "You break it, you fix it" Peter D. Aplan Blood 2005 105: 1843-1844. [Full Text] [PDF] This article has been cited by other articles: C. Bueno, P. Catalina, G. J. Melen, R. Montes, L. Sanchez, G. Ligero, J. L. Garcia-Perez, and P. Menendez Etoposide induces MLL rearrangements and other chromosomal abnormalities in human embryonic stem cells Carcinogenesis, September 1, 2009; 30(9): 1628 - 1637. [Abstract] [Full Text] [PDF] R. K. Slany The molecular biology of mixed lineage leukemia Haematologica, July 1, 2009; 94(7): 984 - 993. [Abstract] [Full Text] [PDF] G. Wang, S. Carbajal, J. Vijg, J. DiGiovanni, and K. M. Vasquez DNA Structure-induced Genomic Instability In Vivo J Natl Cancer Inst, December 17, 2008; 100(24): 1815 - 1817. [Abstract] [Full Text] [PDF] D. P. Harper and P. D. Aplan Chromosomal Rearrangements Leading to MLL Gene Fusions: Clinical and Biological Aspects Cancer Res., December 15, 2008; 68(24): 10024 - 10027. [Abstract] [Full Text] [PDF] M. A. Lichtman Is There an Entity of Chemically Induced BCR-ABL-Positive Chronic Myelogenous Leukemia? Oncologist, June 1, 2008; 13(6): 645 - 654. [Abstract] [Full Text] [PDF] S. B. van Waalwijk van Doorn-Khosrovani, J. Janssen, L. M. Maas, R. W.L. Godschalk, J. G. Nijhuis, and F. J. van Schooten Dietary flavonoids induce MLL translocations in primary human CD34+ cells Carcinogenesis, August 1, 2007; 28(8): 1703 - 1709. [Abstract] [Full Text] [PDF] J. D. Dickerman The Late Effects of Childhood Cancer Therapy Pediatrics, March 1, 2007; 119(3): 554 - 568. [Abstract] [Full Text] [PDF] C. G. Moneypenny, J. Shao, Y. Song, and E. P. Gallagher MLL rearrangements are induced by low doses of etoposide in human fetal hematopoietic stem cells Carcinogenesis, April 1, 2006; 27(4): 874 - 881. [Abstract] [Full Text] [PDF]

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