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Blood, 1 April 2008, Vol. 111, No. 7, pp. 3802-3812. Prepublished online as a Blood First Edition Paper on January 14, 2008; DOI 10.1182/blood-2007-07-096065. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-07-096065v1 111/7/3802    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 CrossRef Google Scholar Articles by Robinson, B. W. Articles by Felix, C. A. PubMed PubMed Citation Articles by Robinson, B. W. Articles by Felix, C. A. Related Collections Oncogenes and Tumor Suppressors Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  NEOPLASIA Prospective tracing of MLL-FRYL clone with low MEIS1 expression from emergence during neuroblastoma treatment to diagnosis of myelodysplastic syndrome Blaine W. Robinson1, Nai-Kong V. Cheung2, Christos P. Kolaris1, Suresh C. Jhanwar3, John K. Choi4, Neil Osheroff5, and Carolyn A. Felix1,6 1 Division of Oncology, The Children's Hospital of Philadelphia, PA; 2 Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY; 3 Cytogenetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY; 4 Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia; 5 Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN; and 6 Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia We prospectively observed a child exposed to intensive multimodality therapy for metastatic neuroblastoma from emergence of a MLL translocation to disease diagnosis. The t(4;11)(p12;q23) was detected in the marrow 17 months after starting treatment following topoisomerase II poisons, alkylating agents, local radiation, hematopoietic stem cell transplantation, anti-GD2 monoclonal antibody with granulocyte macrophage–colony-stimulating factor, and a high cumulative dose of oral etoposide. Reciprocal genomic breakpoint junctions and fusion transcripts joined MLL with FRYL, the Drosophila melanogaster protein homologue of which regulates cell fate. Etoposide metabolites induced topoisomerase II cleavage complexes that could form both breakpoint junctions. Cells harboring the translocation replaced the marrow without clinical evidence of leukemia and differentiation appeared unaffected for 37 months. Subsequent bilineage dysplasia and increased blasts in addition to the translocation fulfilled criteria for MDS. The MEIS1 target gene of typical MLL fusion oncoproteins was underexpressed before and at MDS diagnosis. These results are consistent with repair of topoisomerase II cleavage from etoposide metabolites as the translocation mechanism, whereas other agents in the regimen may have contributed to progression of the clone with the translocation to MDS. MLL-FRYL did not increase MEIS1 expression, conferred a proliferative advantage without altering differentiation, and had protracted latency to disease. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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