Abstract
Chromosomal translocation t(11;17)(q23;21) is associated with a retinoic acid-resistant form of acute promyelocytic leukemia. The translocation fuses the RARalpha gene to the PLZF gene, resulting in the formation of reciprocal fusion proteins, hypothesized to play prominent roles in leukemogenesis. Promyelocytic leukemia zinc finger (PLZF) encodes a transcription factor with nine Krüppel-like zinc fingers, seven of which are retained in the t(11;17) fusion protein RARalpha-PLZF. We identified a specific DNA-binding site for the PLZF protein and showed that PLZF binds to this site through its most carboxyl seven zinc fingers. In co-transfection experiments, PLZF repressed transcription through its cognate binding site. This repression function of PLZF was mapped to two regions on the protein, including the evolutionarily conserved POZ domain. In contrast, the RARalpha-PLZF protein activated transcription of a promoter containing a PLZF response element. These results suggest that RARalpha-PLZF, generated in acute promyelocytic leukemia, is an aberrant transcription factor that can deregulate the expression of PLZF target genes and contribute to leukemogenesis.
Highlights
Chromosomal translocation t(11;17)(q23;21) is associated with a retinoic acid-resistant form of acute promyelocytic leukemia
The RAR␣-Promyelocytic leukemia zinc finger (PLZF) protein activated transcription of a promoter containing a PLZF response element. These results suggest that RAR␣-PLZF, generated in acute promyelocytic leukemia, is an aberrant transcription factor that can deregulate the expression of PLZF target genes and contribute to leukemogenesis
Electrophoretic Mobility Shift Assay (EMSA) assays with the 15A probe, indicated that the binding was relatively nonspecific as binding could be competed with an excess of unlabeled GAL4
Summary
Chromosomal translocation t(11;17)(q23;21) is associated with a retinoic acid-resistant form of acute promyelocytic leukemia. A rare form of APL associated with t(11;17) (19 –21) is resistant to ATRA and conventional chemotherapy In these cases the RAR␣ gene is broken prior to the third coding exon and joined to the PLZF (promyelocytic leukemia zinc finger) gene yielding a fusion protein linking the N-terminal 455 amino acids of PLZF to the B–F domain of RAR␣, including the DNA binding and ligand binding portions of the nuclear receptor. Like PML-RAR␣, PLZF-RAR␣ is a ligand-dependent factor with altered transcriptional activity, and both proteins act in a dominant negative manner to inhibit the full transcriptional function of wild-type RAR␣ [6, 7, 9, 23, 24, 26, 27] These similarities do not explain why t(11;17) patients are resistant to therapy, suggesting that the disruption of the PLZF gene plays a role in the clinical phenotype.
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