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

Overview

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.

publication date

  • January 14, 2008

Research

keywords

  • Gene Expression Regulation, Neoplastic
  • Homeodomain Proteins
  • Myelodysplastic Syndromes
  • Myeloid-Lymphoid Leukemia Protein
  • Neoplasm Proteins
  • Neuroblastoma
  • Oncogene Proteins, Fusion

Identity

PubMed Central ID

  • PMC1895804

Scopus Document Identifier

  • 43549112363

Digital Object Identifier (DOI)

  • 10.1182/blood-2007-07-096065

PubMed ID

  • 18195096

Additional Document Info

volume

  • 111

issue

  • 7