In line with these observations, RA-resistant murine PLZF/RARalpha+RARalpha/PLZFAPL blasts express much higher levels of CRABPI than standard RA-sensitive PML/RARalpha APL.
This paper describes two cases of APL associated with the PLZF-RARA fusion gene enrolled in the IC-APL trial that is a non-randomized, multicenter study conducted in Brazil, Mexico, Chile and Uruguay with the aim to improve the treatment outcome of APL patients in developing countries.
We demonstrate that RARalpha-PLZF can interfere with PLZF transcriptional repression and that this is critical for APL pathogenesis, since leukemias in PLZF(-/-)/PLZF-RARalpha mutants and in PLZF-RARalpha/RARalpha-PLZF TM are indistinguishable.
Compared with the wild-type protein, the binding of the APL-associated reciprocal RARalpha-PLZF fusion to PLZF-RE was much stronger, suggesting that the N-terminal PLZF sequences missing from the fusion may play a role in the regulation of DNA binding.
These data clearly establish the leukemogenic role of PLZF-RARalpha and NPM-RARalpha and the importance of fusion receptor/corepressor interactions in the pathogenesis as well as in determining different clinical phenotypes of APL.
Human acute promyelocytic leukemias (APLs) are associated with chromosomal translocations that replace the NH2 terminus of wild-type retinoic acid receptor (RAR) alpha with portions of the promyelocytic leukemia protein (PML) or promyelocytic leukemia zinc-finger protein (PLZF).
In acute promyelocytic leukemia (APL) cells with rearrangement of retinoic acid receptor a (RAR alpha) (including: PML-RAR alpha, PLZF-RAR alpha, NPM-RAR alpha, NuMA- RAR alpha or STAT5b-RAR alpha) as a result of chromosomal translocations, the RA signal pathway is disrupted and myeloid differentiation is arrested at the promyelocytic stage.
Furthermore, APL associated with translocation between the RARalpha and the PLZF genes (PLZF-RARalpha) shows a distinctly worse prognosis with poor response to chemotherapy and little or no response to treatment with RA, thus defining a new APL syndrome.
Taken together, these data provide novel insights into the mechanisms involved in As2O3-induced apoptosis in APL and predict that treatment of t(11;17) (PLZF-RARalpha-positive) APLs with As2O3 will not be successful.
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.
The variant t(11;17) translocation produces two fusion proteins, promyelocytic leukemia zinc finger-retinoic acid receptor α (PLZF-RARα) and RARα-PLZF, both of which participate in leukemia development.
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.
Taken together, our results demonstrate involvement of nuclear receptor corepressor/histone deacetylase complex in the molecular pathogenesis of APL and provide an explanation for differential sensitivities of PML- and PLZF-RARalpha-associated leukemias to ATRA.
These different protein-protein interactions and the target gene specificities of PLZF-RARalpha and PML-RARalpha may underlie, at least in part, the apparent resistance of APL with t(11;17) to differentiation effects of all-trans-retinoic acid.
These data indicate that a physical interaction between LAZ3 and PLZF underlies their simultaneous recruitment onto multiproteic nuclear complexes, presumably involved in transcriptional silencing and whose integrity (for APL) and/or function (for APL and NHL) may be altered in oncogenesis.
The comparison of the biological activities mediated by PML-RAR alpha and PLZF-RAR alpha may give new insights into the pathogenesis as well as the mechanisms of ATRA-induced differentiation in APL.
The transcriptions of the proapoptotic genes, insulin-like growth factor binding protein 3 (IGFBP3) and BCL2-interacting killer (BIK), were suppressed by ZNF179 via its interaction with the promyelocytic leukemia zinc finger (PLZF) protein in astrocytes.
The PLZF gene was discovered by studying a rearrangement of the RAR alpha locus in a patient with acute promyelocytic leukemia and a t(11;17) chromosomal translocation.
As an approach to silencing estrogen-regulated genes, we have studied the activities of a fusion protein between ERalpha and the promyelocytic leukemia zinc-finger (PLZF) protein, a transcriptional repressor that acts through chromatin remodeling.