Target acquisition and acute promyelocytic leukemia.

promyelocytic leukemia (APL) is characterized by a variety of chromoso-mal translocations into the retinoic acid receptor-α (RARα) gene. The first of these cloned was t(15;17), a transloca-tion that results in fusion of the PML gene with RARα. This translocation is also the most prevalent, found in 95% of APL cases. Other translocations associated with fusion proteins in variant APLs were subsequently discovered: t(11;17) PLZF-RARα (found in less than 5% of cases), another t(11;17) translocation, NuMA-RARα (less than 1%), and t(5;17) NPM-RARα (less than 1%). All of these, with the exception of the PLZF-RARα translocation, are associated with a disease that responds to high doses of retinoids (1). The realization that all of these translocations involved RARα led to the proposal that the disease is caused by dysfunctional regulation of retinoid-inducible genes critical to myeloid differentiation. Recent work supporting this idea has shown that PML-RARα has a reduced ability to release transcrip-tional corepressors such as SMRT and NCoR in response to retinoids and that the PLZF portion of the PLZF-RARα fusion constitutively binds these repres-sors (2, 3). This would suggest that in APL cells, RARα target genes may be transcriptionally super-repressed, and may also explain why PML-RARα APL responds to high doses of retinoids, whereas PLZF-RARα APL is retinoid resistant. The ultimate proof of the hypothesis, however, has awaited the identification of critical target genes, the regulation of which is disrupted by the fusion proteins. In this issue of the JCI, Park et al. propose that the gene for the myeloid-specific transcription factor C/EBPε may be such a target (4). Previous studies have shown that C/EBPε transcription is induced by retinoids during granulocytic, but not monocytic, differentiation (5). Mice in which the gene is deleted exhibit impaired granulopoiesis (6). Therefore C/EBPε has many of the predicted characteristics of a critical target gene in APL. It remained to be demonstrated that its promoter contained a functional retinoic acid response element (RARE) and that overexpression of C/EBPε alone was sufficient to induce granulocytic differentiation. These key experiments are presented in this issue. The authors identified a RARE in the C/EBPε promoter and showed it to be functional in transfection assays. They demonstrated that C/EBPε expression could be induced in a ligand-dependent manner by PML-RARα (a fusion product found in a retinoid-sensitive APL) but not by PLZF-RARα (a fusion product found in a retinoid-resistant APL). Overexpression of C/EBPε in U937 cells was then shown …