Etoposide induces chimeric Mll gene fusions

FASEB J. 2004 Jan;18(1):173-5. doi: 10.1096/fj.03-0638fje. Epub 2003 Nov 20.

Abstract

MLL gene fusions are the hallmark of more than 70% of therapy-related leukemias (t-ML) associated with topoisomerase II inhibitors (e.g., etoposide) and cause leukemia in murine transgenic models. To determine whether Mll genomic fusions can occur after exposure to topoisomerase II inhibitors, we developed a long-distance inverse PCR DNA-based assay for chimeric Mll fusions in mouse embryonic stem cells. We detected Mll fusions at a higher frequency following 100 microM etoposide for 8 h (16x10(-6) cell(-1)) than in no-drug controls (1.0x10(-6) cell(-1), P=0.0002) or after treatment with a comparably cytotoxic exposure to the antimicrotubule drug vincristine (1.0x10(-6) cell(-1), P=0.0047). The fusion points in Mll chimeric products induced by etoposide were localized to a 1.5 kb region between exons 9 and 11, analogous to the MLL breakpoint cluster region in human leukemia. All 49 Mll fusion partners analyzed matched known genomic murine sequences, with 40 (82%) matching annotated genes covering eighteen murine autosomes. One partner was Runx1, the murine homologue of the transcription factor AML-1, a target of human translocations in therapy-related leukemia. These findings indicate that etoposide triggers the formation of Mll gene fusions, a critical step for the development of treatment-induced leukemic transformation.

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / toxicity*
  • Artificial Gene Fusion
  • DNA-Binding Proteins / genetics*
  • Enzyme Inhibitors / toxicity
  • Etoposide / toxicity*
  • Histone-Lysine N-Methyltransferase
  • Humans
  • Leukemia / chemically induced
  • Leukemia / genetics
  • Mice
  • Myeloid-Lymphoid Leukemia Protein
  • Oncogene Proteins, Fusion / genetics*
  • Proto-Oncogenes*
  • Topoisomerase II Inhibitors
  • Transcription Factors*

Substances

  • Antineoplastic Agents, Phytogenic
  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • KMT2A protein, human
  • Oncogene Proteins, Fusion
  • Topoisomerase II Inhibitors
  • Transcription Factors
  • Myeloid-Lymphoid Leukemia Protein
  • Etoposide
  • Histone-Lysine N-Methyltransferase
  • Kmt2a protein, mouse