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 language||English (US)|
|Number of pages||14|
|State||Published - Feb 14 1996|
- Zinc finger
ASJC Scopus subject areas
- Molecular Biology
- Cancer Research