Fusion genes resulting from alternative chromosomal translocations are overexpressed by gene-specific mechanisms in alveolar rhabdomyosarcoma

Proc Natl Acad Sci U S A. 1997 Jul 22;94(15):8047-51. doi: 10.1073/pnas.94.15.8047.

Abstract

Chromosomal translocations identified in hematopoietic and solid tumors result in deregulated expression of protooncogenes or creation of chimeric proteins with tumorigenic potential. In the pediatric solid tumor alveolar rhabdomyosarcoma, a consistent t(2;13)(q35;q14) or variant t(1;13)(p36;q14) translocation generates PAX3-FKHR or PAX7-FKHR fusion proteins, respectively. In this report, we demonstrate that in addition to functional alterations these translocations are associated with fusion product overexpression. Furthermore, PAX3-FKHR and PAX7-FKHR overexpression occurs by distinct mechanisms. Transcription of PAX3-FKHR is increased relative to wild-type PAX3 by a copy number-independent process. In contrast, PAX7-FKHR overexpression results from fusion gene amplification. Thus, gene-specific mechanisms were selected to overexpress PAX3-FKHR and PAX7-FKHR in alveolar rhabdomyosarcoma, presumably due to differences in regulation between the wild-type loci. We postulate that these overexpression mechanisms ensure a critical level of gene product for the oncogenic effects of these fusions.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Chromosomes, Human, Pair 1*
  • Chromosomes, Human, Pair 13*
  • Chromosomes, Human, Pair 2*
  • Cloning, Molecular*
  • DNA-Binding Proteins / genetics
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Homeodomain Proteins*
  • Humans
  • Muscle Proteins / genetics
  • Nerve Tissue Proteins / genetics
  • PAX3 Transcription Factor
  • PAX7 Transcription Factor
  • Paired Box Transcription Factors
  • Rhabdomyosarcoma, Alveolar / genetics*
  • Transcription Factors / genetics
  • Transcriptional Activation
  • Translocation, Genetic*
  • Tumor Cells, Cultured

Substances

  • DNA-Binding Proteins
  • FOXO1 protein, human
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Homeodomain Proteins
  • Muscle Proteins
  • Nerve Tissue Proteins
  • PAX3 Transcription Factor
  • PAX3 protein, human
  • PAX7 Transcription Factor
  • PAX7 protein, human
  • Paired Box Transcription Factors
  • Transcription Factors
  • Pax3 protein, mouse