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A bcr-3 isoform of RARalpha-PML potentiates the development of PML-RARalpha-driven acute promyelocytic leukemia.

Acute promyelocytic leukemia (APML) most often is associated with the balanced reciprocal translocation t(15;17) (q22;q11.2) and the expression of both the PML-RARalpha and RARalpha-PML fusion cDNAs that are formed by this translocation. In this report, we investigated the biological role of a bcr-3 isoform of RARalpha-PML for the development of APML in a transgenic mouse model. Expression of RARalpha-PML alone in the early myeloid cells of transgenic mice did not alter myeloid development or cause APML, but its expression significantly increased the penetrance of APML in mice expressing a bcr-1 isoform of PML-RARalpha (15% of animals developed APML with PML-RARalpha alone vs. 57% with both transgenes, P < 0.001). The latency of APML development was not altered substantially by the expression of RARalpha-PML, suggesting that it does not behave as a classical "second hit" for development of the disease. Leukemias that arose from doubly transgenic mice were less mature than those from PML-RARalpha transgenic mice, but they both responded to all-trans retinoic acid in vitro. These findings suggest that PML-RARalpha drives the development of APML and defines its basic phenotype, whereas RARalpha-PML potentiates this phenotype via mechanisms that are not yet understood.

Pubmed ID: 10611345


  • Pollock JL
  • Westervelt P
  • Kurichety AK
  • Pelicci PG
  • Grisolano JL
  • Ley TJ


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

December 21, 1999

Associated Grants

  • Agency: NCI NIH HHS, Id: CA49712

Mesh Terms

  • Animals
  • Bone Marrow Cells
  • Cathepsins
  • Crosses, Genetic
  • Gene Expression
  • Humans
  • Leukemia, Promyelocytic, Acute
  • Mice
  • Mice, Transgenic
  • Neoplasm Proteins
  • Oncogene Proteins, Fusion
  • Penetrance
  • Phenotype
  • Protein Isoforms
  • Spleen
  • Translocation, Genetic
  • Tretinoin