Prospective tracing of MLL-FRYL clone with low MEIS1 expression from emergence during neuroblastoma treatment to diagnosis of myelodysplastic syndrome Journal Article


Authors: Robinson, B. W.; Cheung, N. K. V.; Kolaris, C. P.; Jhanwar, S. C.; Choi, J. K.; Osheroff, N.; Felix, C. A.
Article 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 pro- tracted latency to disease.© 2008 by The American Society of Hematology.
Keywords: controlled study; protein expression; unclassified drug; oncoprotein; gene translocation; human cell; genetics; busulfan; case report; cisplatin; doxorubicin; multimodality cancer therapy; combined modality therapy; cytarabine; methotrexate; topotecan; antineoplastic agent; prospective study; prospective studies; chromosome 12; animal; metabolism; animals; gene targeting; carboplatin; multiple cycle treatment; gene expression; bone marrow; etoposide; antineoplastic combined chemotherapy protocols; granulocyte macrophage colony stimulating factor; neoplasm proteins; cell fate; alkylating agent; cyclophosphamide; melphalan; vincristine; hematopoietic stem cell transplantation; homeodomain proteins; drug effect; pathology; thiotepa; monoclonal antibody; gene expression regulation; gene expression regulation, neoplastic; biosynthesis; antibodies, monoclonal; drug antagonism; myelodysplastic syndrome; sequence homology, amino acid; neuroblastoma; nucleotide sequence; tumor protein; fusion gene; oncogene proteins, fusion; asparaginase; chromosome breakage; chromosome translocation; translocation, genetic; drosophila melanogaster; homeodomain protein; isotretinoin; sequence homology; drug metabolite; alkylating agents; dna topoisomerase (atp hydrolysing); tacrolimus; peripheral blood stem cell transplantation; transplantation, autologous; monoclonal antibody 3f8; dna topoisomerases, type ii; myelodysplastic syndromes; blast cell; clone; autotransplantation; granulocyte-macrophage colony-stimulating factor; chromosome 4; chromosomes, human, pair 4; mixed lineage leukemia protein; myeloid-lymphoid leukemia protein; mll protein, human; myeloid ecotropic viral integration site 1 protein; meis1 gene; mll fryl gene; chromosomes, human, pair 12
Journal Title: Blood
Volume: 111
Issue: 7
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2008-04-01
Start Page: 3802
End Page: 3812
Language: English
DOI: 10.1182/blood-2007-07-096065
PUBMED: 18195096
PROVIDER: scopus
PMCID: PMC2275033
DOI/URL:
Notes: --- - "Cited By (since 1996): 2" - "Export Date: 17 November 2011" - "CODEN: BLOOA" - "Molecular Sequence Numbers: GENBANK: AAG41424, DQ299934, DQ299935, DQ299936, DQ299937, DQ299938, DQ299939, DQ299940, L04284, NM_015030, U04737;" - "Source: Scopus"
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MSK Authors
  1. Nai-Kong Cheung
    447 Cheung
  2. Suresh C Jhanwar
    217 Jhanwar