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Collins From the Molecular Medicine Division, Fred Hutchinson Cancer Research Center, Seattle, WA.     ARTICLE Article References 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 RAR on chromosome 17. Indeed, cytogenetic or molecular evidence for the presence of this PML-RAR 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-RAR 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-RAR fusion protein leads to leukemia, the PML-RAR product may compete with the normal RAR for binding to RXR and thus interfere with normal RXR-RAR heterodimer formation in a dominant negative manner.12 View larger version (28K): [in this window] [in a new window]   Fig 1. (A) The retinoic acid receptors, RXR and RAR, harbor distinct DNA-binding domains (DBD) and ligand-binding domains (LBD) and bind as a heterodimer to a specific direct repeat separated by 5 bp making up the retinoic acid response element (RARE). (B) In the absence of ligand, the RXR-RAR heterodimer associates with a transcriptional repressor complex, including N-CoR, mSin3a, and a histone deacetylase (HDAC-1). (C) The addition of all-trans retinoic acid (ATRA) results in a conformational change in the RXR-RAR heterodimer resulting in the release of the repressor complex and recruitment of a transcriptional activator complex exhibiting histone acetyltransferase activity and associated transcriptional activation. An unusual variant of APL is associated with t(11;17), which fuses RAR to a gene on chromosome 11 termed promyelocytic leukemia zinc finger (PLZF). Although the PLZF-RAR leukemias morphologically and histochemically resemble the PML-RAR leukemias, in marked contrast to the PML-RAR 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-RAR versus the PLZF-RAR 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-RAR and PML-RAR fusion proteins. First, PLZF, like RAR, but unlike PML, binds the transcriptional corepressor N-CoR. Thus, N-CoR can potentially bind both the RAR and PLZF regions of the chimeric PLZF-RAR fusion protein. In addition, Guidez et al15 demonstrate that this PLZF-RAR 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-RAR fusion protein. These differences in protein-protein interactions were demonstrated in vitro on glutathione sepharose beads and in vivo in yeast, but the implications for leukemia cells are clear. In PML-RAR leukemias, the addition of retinoic acid dissociates the N-CoR-mSin3-HDAC transcriptional repressor complex from PML-RAR, which relieves transcriptional repression and presumably activates genes involved in terminal differentiation of the promyelocytes. In contrast, in the PLZF-RAR 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 the importance of the N-Cor, mSin3-HDAC transcriptional repression complex in maintaining the leukemic state. Although these experiments provide persuasive biochemical evidence for the striking difference in the clinical behavior of the PLZF-RAR versus the PML-RAR leukemias, several critical questions remain. Why are such translocations involving RAR confined to the promyelocytic leukemias? The absence of RAR fusion proteins in any other type of leukemia suggests that translocations involving RAR are only leukemogenic in lineage-committed promyelocytes rather than in more immature hematopoietic progenitors, but the molecular basis for this discrepancy remains unclear. What is the normal function of the PML and PLZF proteins and why do these proteins predominate as the fusion partners for RAR in the promyelocytic leukemias? The sequence of these genes suggest they might act as DNA-binding transcription factors, and, under certain experimental conditions, PLZF and PML colocalize to specific nuclear multiprotein structures, the nuclear bodies (NBs).16 However, the specific genes that the PML and PLZF proteins might normally regulate remain unknown. Finally, if transcriptional repression is critical to maintaining the leukemic state as these experiments suggest, then what are the specific target genes that are being repressed in the leukemia cells? To put it another way, what are the genes that are activated by retinoic acid in the PML-RAR leukemias that trigger their terminal differentiation? Such target genes remain elusive, but their identification will be crucial to understanding why APL cells can be induced to undergo terminal granulocytic differentiation by retinoic acid whereas most other acute leukemias cannot.     FOOTNOTES       Address reprint requests to Steven J. Collins, MD, Fred Hutchinson Cancer Research Center, Molecular Medicine Division, 1100 Fairview Ave N, Suite C2-023, Seattle, WA 98109.     REFERENCES Article References 1. Breitman T, Collins S, Keene B: Terminal differentiation of human promyelocytic leukemia cells in primary culture in response to retinoic acid. Blood 57:1000, 1981[Abstract/Free Full Text] 2. Huang M, Ye Y, Chen S, Chai J, Lu J, Zhoa L, Gu L, Wang Z: Use of all trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 72:567, 1988[Abstract/Free Full Text] 3. Castaigne S, Chomienne C, Daniel M, Berger N, Fenaux P, Degos L: All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I. Clinical Results. Blood 76:1704, 1990[Abstract/Free Full Text] 4. Warrell R, Frankel S, Miller W, Itri L, Andreef M, Jabukowski A, Gabrilove J, Gordon M, Dmitrovsky E: Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans retinoic acid). N Engl J Med 324:1385, 1990[Abstract] 5. Degos L, Dombret H, Chomienne C, Daniel M, Miclea J, Chastang C, Castaigne S, Fenaux P: All trans-retinoic acid as a differentiating agent in the treatment of acute promyelocytic leukemia. Blood 85:2643, 1995[Free Full Text] 6. Tallman M, Andersen J, Schiffer C, Appelbaum F, Feusner J, Ogden A, Shepherd L, Willman C, Bloomfield C, Rowe J, Wiernik P: All-trans retinoic acid in acute promyelocytic leukemia. N Engl J Med 337:1021, 1997[Abstract/Free Full Text] 7. Horlein A, Naar A, Heinzel T, Torchia J, Gloss B, Kurokawa R, Ryan A, Kamei Y, Soderstrom M, Glass C, Rosenfeld M: Ligand-independent repression by the thyroid hormone receptor mediated by a nuclear receptor co-repressor. Nature 377:397, 1995[Medline] [Order article via Infotrieve] 8. Heinzel T, Lavinsky R, Mullen T, Soderstrom M, Laherty C, Torchia J, Yang W-M, Brard G, Ngo S, Davie J, Seto E, Eisenman R, Rose D, Glass C, Rosenfeld M: A complex containing N-CoR, mSin3 and histone deacetylase mediates transcriptional repression. Nature 387:43, 1997[Medline] [Order article via Infotrieve] 9. Kamei Y, Xu L, Heinzel T, Torchia J, Kurokawa R, Gloss B, Lin S-C, Heyman R, Rose D, Glass C, Rosenfeld M: A CBP integrator complex mediates transcriptional activation and AP-1 inhibition by nuclear receptors. Cell 85:403, 1996[Medline] [Order article via Infotrieve] 10. Chakravarti D, LaMorte V, Nelson M, Nakajima T, Schulman I, Juguilon H, Montminy M, Evans R: Role of CBP/p300 in nuclear receptor signaling. Nature 383:99, 1996[Medline] [Order article via Infotrieve] 11. Chen H, Lin R, Schiltz R, Chakravarti D, Nash A, Nagy L, Privalsky M, Nakatani Y, Evans R: Nuclear receptor coactivator ACTR is a novel histone acetyltransferase and forms a multimeric activation complex with P/CAF and CBP/p300. Cell 90:569, 1997[Medline] [Order article via Infotrieve] 12. Perez A, Kastner P, Sethi S, Lutz Y, Reibel C, Chambon P: PMLRAR homodimers: Distinct DNA properties and heteromeric interactions with RXR. EMBO J 12:3171, 1993[Medline] [Order article via Infotrieve] 13. Chen Z, Brand N, Chen A, Chen S-J, Tong J-H, Wang Z-Y, Waxman S, Zelent A: Fusion between a novel Kruppel-like zinc finger gene and the retinoic acid receptor- locus due to a variant t(11;17) translocation associated with acute promyelocytic leukemia. EMBO J 12:1161, 1993[Medline] [Order article via Infotrieve] 14. Chen Z, Guidez F, Rousselot P, Agadir A, Chen S-J, Wang Z-Y, Degos L, Zelent A, Waxman S, Chomienne C: PLZF-RAR fusion proteins generated from the variant t(11;17)(q23;21) translocation in acute promyelocytic leukemia inhibit ligand-dependent transactivation of wild-type retinoic acid receptors. Proc Natl Acad Sci USA 91:1178, 1994[Abstract/Free Full Text] 15. Guidez F, Ivins S, Zhu J, Söderström M, Waxman S, Zelent A: Reduced retinoic acid-sensitivities of nuclear receptor corepressor binding to PML and PLZF-RAR underlie molecular pathogenesis and treatment of acute promyelocytic leukemia. Blood 91:2634, 1998[Abstract/Free Full Text] 16. Koken M, Reid A, Quignon F, Chelbi-Alix M, Davies J, Kabarowsi J, Zhu J, Dong S, Chen S, Chen Z, Tan C, Licht J, Waxman S, de The H, Zelent A: Leukemia-associated retinoic acid receptor  fusion partners, PML and PLZF, heterodimerize and colocalize to nuclear bodies. Proc Natl Acad Sci USA 94:10255, 1997[Abstract/Free Full Text] © 1998 by The American Society of Hematology.   0006-4971/98/91-0055$3.00/0 CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: F. M. Denis, A. Benecke, Y. Di Gioia, I. P. Touw, Y. E. Cayre, and P. G. Lutz PRAM-1 Potentiates Arsenic Trioxide-induced JNK Activation J. Biol. Chem., March 11, 2005; 280(10): 9043 - 9048. [Abstract] [Full Text] [PDF] Z.-y. Wang Ham-Wasserman Lecture: Treatment of Acute Leukemia by Inducing Differentiation and Apoptosis Hematology, January 1, 2003; 2003(1): 1 - 13. [Abstract] [Full Text] [PDF] Y. Jing, L. Xia, and S. Waxman Targeted removal of PML-RARalpha protein is required prior to inhibition of histone deacetylase for overcoming all-trans retinoic acid differentiation resistance in acute promyelocytic leukemia Blood, July 18, 2002; 100(3): 1008 - 1013. [Abstract] [Full Text] [PDF] T.-X. Liu, J.-W. Zhang, J. 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	Copyright © 1998 by American Society of Hematology         Online ISSN: 1528-0020