Acute promyelocytic leukemia: relieving repression induces remission.

RETINOIDS AND IN particular retinoic acid are naturally occurring compounds that regulate the growth and differentiation of a variety of different cell types. The observation that retinoic acid induces the terminal differentiation of human acute promyelocytic leukemia (APL) cells both in vitro1 and in vivo2-4 has had a significant impact in clinical hematology and has altered our approach to therapy for this subtype of acute myelocytic leukemia (AML). Indeed, the addition of retinoic acid to conventional chemotherapy increases the apparent cure rate for patients with APL.5,6 The biologic effects of retinoic acid are generally mediated through specific ligand activated nuclear transcription factors, the retinoic acid receptors (RARs). Interestingly, the great majority of APLs exhibit a characteristic t(15;17) chromosome translocation that generates an aberrant RAR consisting of a chimeric protein fusing a portion of the PML gene on chromosome 15 with RARa on chromosome 17. Indeed, cytogenetic or molecular evidence for the presence of this PML-RARa fusion protein in patient leukemia cells is perhaps the best predictor of initial patient response to retinoic acid. The molecular mechanisms underlying retinoic acid and RAR activity and how this may be disrupted in the PML-RARa APLs has been the subject of considerable investigation. The retinoic acid receptors consist of two distinct families, the RARs and RXRs, both exhibiting modular structures harboring distinct DNA binding and ligand binding domains. These receptors likely mediate their biologic effects by binding as RAR-RXR heterodimers to specific regulatory elements (RAREs), in particular target genes (Fig 1A). The RAR-RXR heterodimer interacts in the absence of ligand with a large ubiquitous nuclear protein (N-CoR), which mediates transcriptional repression through its interaction with other proteins, including mSin3A and histone deacetylase (HDAC)7,8 (Fig 1B). A current model explaining RAR activity suggests that the addition of ligand (RA) results in a distinct conformational change in the RAR-RXR complex, resulting in the release of the repressor protein complex and recruitment of transcriptional coactivators (Fig 1C).9-11 Thus, the addition of ligand (RA) normally converts RAR-RXR from a transcriptional repressor (Fig 1B) to a transcriptional activator (Fig 1C). Although it is presently unclear exactly how the expression of the aberrant PML-RARa fusion protein leads to leukemia, the PML-RARa product may compete with the normal RARa for binding to RXR and thus interfere with normal RXR-RARa heterodimer formation in a dominant negative manner.12 An unusual variant of APL is associated with t(11;17), which fuses RARa to a gene on chromosome 11 termed promyelocytic leukemia zinc finger (PLZF). Although the PLZF-RARa leukemias morphologically and histochemically resemble the PMLRARa leukemias, in marked contrast to the PML-RARa leukemias, they are invariably resistant to retinoic acid and exhibit no differentiative/therapeutic response to this compound.13,14 In the present issue of Blood, Guidez et al15 now offer a molecular basis for this marked difference in the clinical response to retinoic acid of the PML-RARa versus the PLZFRARa promyelocytic leukemias. In a series of convincing experiments, they demonstrate several major differences in the biochemical interactions of the N-CoR transcriptional repressor with the leukemia-specific PLZF-RARa and PML-RARa fusion proteins. First, PLZF, like RARa, but unlike PML, binds the transcriptional corepressor N-CoR. Thus, N-CoR can potentially bind both the RARa and PLZF regions of the chimeric PLZF-RARa fusion protein. In addition, Guidez et al15 demonstrate that this PLZF-RARa binding to N-CoR continues even in the presence of relatively high pharmacological (1 to 10 μmol/L) concentrations of retinoic acid. In contrast, the same concentrations of retinoic acid appear to dissociate N-CoR from the PML-RARa fusion protein. These differences in proteinprotein interactions were demonstrated in vitro on glutathione sepharose beads and in vivo in yeast, but the implications for leukemia cells are clear. In PML-RARa leukemias, the addition of retinoic acid dissociates the N-CoR-mSin3-HDAC transcriptional repressor complex from PML-RARa, which relieves transcriptional repression and presumably activates genes involved in terminal differentiation of the promyelocytes. In contrast, in the PLZF-RARa leukemias, retinoic acid, even in relatively high doses, does not dissociate this complex and transcriptional repression is maintained, which presumably maintains the relatively undifferentiated leukemic state of the cells. Thus, these experiments provide a biochemical explanation for the marked difference in the clinical response of these subsets of promyelocytic leukemia to retinoids and emphasize