Leukemia initiated by PMLRARα: The PML domain plays a critical role while retinoic acid-mediated transactivation is dispensable

Scott C. Kogan, Suk Hyun Hong, David B. Shultz, Martin L. Privalsky, J. Michael Bishop

Research output: Contribution to journalArticlepeer-review

81 Scopus citations

Abstract

The most common chromosomal translocation in acute promyelocytic leukemia (APL), 115;17(q22;q21), creates PMLRARα and RARαPML fusion genes. We previously developed a mouse model of APL by expressing PMLRARα in murine myeloid cells. In order to examine the mechanisms by which PMLRARα can initiate leukemia, we have now generated transgenic mice expressing PMLRARαm4 and RARαm4, proteins that are unable to activate transcription in response to retinoic acid. PMLRARαm4 transgenic mice developed myeloid leukemia, demonstrating that transcriptional activation by PMLRARα Is not required for leukemic transformation. The characteristics of the leukemias arising in the PMLRARαm4 transgenic mice varied from those previously observed in our PMLRARα transgenic mice, indicating that ligand responsiveness may influence the phenotype of the leukemic cells. The leukemias that arose in PMLRARαm4 transgenic mice did not differentiate in response to retinoic acid therapy. This result supports the hypothesis that a major therapeutic effect of retinoic acid is mediated directly through the PMLRARα protein. However, a variable effect on survival suggested that this agent may be of some benefit in APL even when leukemic cells are resistant to its differentiative effects. Transgenic mice expressing high levels of RARαm4 have not developed leukemia, providing evidence that the PML domain of PMLRARα plays a specific and critical role in the pathogenesis of APL. (C) 2000 by The American Society of Hematology.

Original languageEnglish (US)
Pages (from-to)1541-1550
Number of pages10
JournalBlood
Volume95
Issue number5
StatePublished - Mar 1 2000
Externally publishedYes

ASJC Scopus subject areas

  • Hematology

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