Reduced and altered DNA-binding and transcriptional properties of the PLZF-retinoic acid receptor-alpha chimera generated in t(11;17)-associated acute promyelocytic leukemia.
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 Krüppel-like zinc finger protein, is fused to the retinoic acid receptor-alpha (RAR alpha) 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-RAR alpha and RAR alpha-PLZF fusion proteins were localized to the nucleus both in the presence and absence of ATRA. PLZF-RAR alpha, in combination with the retinoid X receptor (RXR) bound to a retinoic acid-responsive element (RARE) less efficiently than RAR alpha and formed multimeric DNA-protein complexes. PLZF-RAR alpha stimulated ATRA-dependent transcription of RARE-containing reporter genes with diminished activity compared to wild-type RAR alpha. In addition, PLZF-RAR alpha antagonized the function of coexpressed wild-type RAR alpha, 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-RAR alpha chimera. However, disruption of the function of the myeloid-specific PLZF protein may also play an important role.
Licht
J D
JD
Brookdale Center for Molecular Biology, Mount Sinai School of Medicine, New York, NY 10029, USA.
Shaknovich
R
R
English
M A
MA
Melnick
A
A
Li
J Y
JY
Reddy
J C
JC
Dong
S
S
Chen
S J
SJ
Zelent
A
A
Waxman
S
S
D001483:Base Sequence; D002880:Chromosomes, Human, Pair 11; D002886:Chromosomes, Human, Pair 17; D004247:DNA / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000032:analysis / Q000502:physiology*; D015321:Gene Rearrangement; D006801:Humans; D051741:Kruppel-Like Transcription Factors; D015473:Leukemia, Promyelocytic, Acute / Q000209:etiology / Q000235:genetics*; D008969:Molecular Sequence Data; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D018168:Receptors, Retinoic Acid / Q000032:analysis / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000032:analysis / Q000502:physiology*; D014157:Transcription Factors / Q000032:analysis / Q000502:physiology*; D014158:Transcription, Genetic; D014178:Translocation, Genetic
D004268:DNA-Binding Proteins; D051741:Kruppel-Like Transcription Factors; D000075722:Promyelocytic Leukemia Zinc Finger Protein; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; C092037:ZBTB16 protein, human; D004247:DNA