Reduced and altered DNA-binding and transcriptional properties of the PLZF-retinoic acid receptor-α chimera generated in t(11;17)-associated acute promyelocytic leukemia

Jonathan D. Licht, Rita Shaknovich, Milton A. English, Ari Melnick, Jia Yuan Li, Josina C. Reddy, Shuo Dong, Sai Juan Chen, Arthur Zelent, Samuel Waxman

Research output: Contribution to journalArticlepeer-review

85 Scopus citations

Abstract

Acute promyelocytic leukemia (APL) associated with chromosomal rearrangement t(11;17) is a distinct syndrome which, unlike typical t(15;17) APL, fails to respond to all-trans retinoic acid (ATRA) therapy. In t(11;17) the PLZF gene, encoding a Kruppel-like zinc finger protein, is fused to the retinoic acid receptor-α (RARα) gene, yielding two classes of chimeric proteins. PLZF protein was found in the nucleus in a punctate speckled pattern that differed from the nuclear body expression pattern of the PML protein affected in t(15;17) APL. The reciprocal PLZF-RARα and RARα-PLZF fusion proteins were localized to the nucleus both in the presence and absence of ATRA. PLZF-RARα, in combination with the retinoid X receptor (RXR) bound to a retinoic acid-responsive element (RARE) less efficiently than RARα and formed multimeric DNA-protein complexes. PLZF-RARα stimulated ATRA-dependent transcription of RARE-containing reporter genes with diminished activity compared to wild-type RARα. In addition, PLZF-RARα antagonized the function of coexpressed wild-type RARα, an effect relieved by over-expression of RXR. Leukemogenesis in t(11;17) APL may be related to interference with ATRA-mediated differentiation due to sequestration of RXR by the PLZF-RARα chimera. However, disruption of the function of the myeloid-specific PLZF protein may also play an important role.

Original languageEnglish (US)
Pages (from-to)323-336
Number of pages14
JournalOncogene
Volume12
Issue number2
StatePublished - 1996

Keywords

  • Leukemia
  • Retinoid
  • Transcription
  • Zinc finger

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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