Submitted July 9, 2007
Accepted January 5, 2008
Prospective tracing of MLL-FRYL clone with low MEIS1 expression from emergence during neuroblastoma treatment to diagnosis of myelodysplastic syndrome
Blaine W Robinson, Nai-Kong V Cheung, Christos P Kolaris, Suresh C Jhanwar, John K Choi, Neil Osheroff, and Carolyn A Felix*
Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA, United States
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY, United States
Department of Medicine, Cytogenetics Service, Memorial Sloan-Kettering Cancer Center, New York, NY, United States
Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA, United States
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, United States
Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, United States
* Corresponding author; email: felix{at}email.chop.edu.
We prospectively followed a child exposed to intensive multi-modality 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 GM-CSF and a high cumulative dose of oral etoposide. Reciprocal genomic breakpoint junctions and fusion transcripts joined MLL with FRYL, the Drosophila 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, while 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.
