title: Prospective tracing of MLL-FRYL clone with low MEIS1 expression from emergence during neuroblastoma treatment to diagnosis of myelodysplastic syndrome.
abstract: 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.
authors.affiliation: Division of Oncology, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine 19104-4318, USA.
authors.forename: Blaine W
authors.initials: BW
authors.lastname: Robinson
authors.forename: Nai-Kong V
authors.initials: NK
authors.lastname: Cheung
authors.forename: Christos P
authors.initials: CP
authors.lastname: Kolaris
authors.forename: Suresh C
authors.initials: SC
authors.lastname: Jhanwar
authors.forename: John K
authors.initials: JK
authors.lastname: Choi
authors.forename: Neil
authors.initials: N
authors.lastname: Osheroff
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Felix
mesh_terms: D000477:Alkylating Agents / Q000008:administration & dosage / Q000009:adverse effects; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D002675:Child, Preschool; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics / Q000378:metabolism; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics / Q000378:metabolism; D003131:Combined Modality Therapy / Q000009:adverse effects; D004250:DNA Topoisomerases, Type II / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster / Q000235:genetics / Q000378:metabolism; D005047:Etoposide / Q000008:administration & dosage / Q000009:adverse effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000009:adverse effects; D011495:Histone-Lysine N-Methyltransferase; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D008297:Male; D009190:Myelodysplastic Syndromes / Q000175:diagnosis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D051788:Myeloid-Lymphoid Leukemia Protein / Q000096:biosynthesis* / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D009447:Neuroblastoma / Q000150:complications / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis* / Q000235:genetics; D036102:Peripheral Blood Stem Cell Transplantation; D011446:Prospective Studies; D017386:Sequence Homology, Amino Acid; D059005:Topoisomerase II Inhibitors; D014178:Translocation, Genetic / Q000235:genetics; D014182:Transplantation, Autologous
chemical_list: D000477:Alkylating Agents; D000911:Antibodies, Monoclonal; D018398:Homeodomain Proteins; C497422:KMT2A protein, human; C000616391:MEIS1 protein, human; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D059005:Topoisomerase II Inhibitors; D051788:Myeloid-Lymphoid Leukemia Protein; D005047:Etoposide; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D011495:Histone-Lysine N-Methyltransferase; D004250:DNA Topoisomerases, Type II