Orchestration of multiple arrays of signal cross-talk and combinatorial interactions for maturation and cell death: another vision of t(15;17) preleukemic blast and APL-cell maturation GeÂrard Benoit 1 , Mathilde Roussel 1 , FreÂdeÂrio Pendino 1 , Evelyne SeÂgal-Bendirdjian 1 and Michel Lanotte* ,1 1 INSERM U-496, Ho Ãpital Saint-Louis, 1, avenue Claude-Vellefaux, 75010 Paris, France Despite intensive molecular biology investigations over the past 10 years, and an important breakthrough on how PML ± RARa, the fusion protein resulting from t(15;17), can alter RARa and PML functions, no de®nitive views on how leukemia is generated and by what mechanism(s) the normal phenotype is restored, are yet available. `Resistances' to pharmacological levels of all-trans-retinoic acid (ATRA) have been observed in experimental in vivo and in vitro models. In this review, we emphasize the key role played by signal cross-talk for both normal and neoplastic hemopoiesis. After an overview of reported experimental data on APL-cell maturation and apoptosis, we apply our current knowl- edge on signaling pathways to underline those which might generate signal cross-talks. The design of biological models suitable to decipher the integration of signal cross-talks at the transcriptional level should be our ®rst priority today, to generate some realistic therapeutic approaches After `Ten Years of Molecular APL', we still know very little about how the disease develops and how eective medicines work. Oncogene (2001) 20, 7161 ± 7177. Keywords: APL; maturation; cell death; ATRA; cyclic AMP; `rexinoids'; RXR signaling; cross-talk Twenty years of intense research eorts have been devoted to acute promyelocytic leukemia (APL) biology and maturation therapy of leukemias (reviewed in Melnick and Licht, 1999): 10 years before the t(15;17) chromosomal translocation was cloned and the fusion protein, PML ± RARa, was identi®ed, and 10 years after these important milestones. It is now tempting to propose the retinoid matura- tion-therapy developed for this pathology as a model applicable to any tumor (Hansen et al., 2000). However, any application of this successful retinoid therapy to other tumor cell types should only be started after taking into account all the speci®cities of the APL cell. Moreover, the particular tissue context in which this pathology develops should also hold our attention. Several speci®c features of the hemopoietic system undoubtedly contribute to the success of retinoid-induced maturation therapy. Hemopoiesis is a developmental process during which cells, at any stage, are subjected to complex humoral and cellular regulations (Dexter et al., 1984; Zipori, 1990; Torok- Storb et al., 1999). Much eort has been devoted to merely trying to understand how retinoid signaling and RARa transcriptional responses are altered in APL. Only rare investigations on the pathophysiology of APL cells have examined the role played by membrane signals on nuclear-receptor functions. The develop- mental biology literature indicates that combinations of signals play essential roles in the cell speci®city of transcriptional responses. This notion should help to transfer to other tumor-cell types the impressive amount of data gathered over the years on APL, and importantly it should also provide explanations as to why retinoid-induced maturation therapy alone fails. In this review, we successively, summarize the hemopoietic context in which APL develops, question the relevance of both the biological materials and the methodological approaches used in our investigations. We present data supporting the role for signaling cross- talk in retinoid-induced maturation and cell death, and, ®nally, we diagram the essential membrane receptor-dependent signaling pathways and their cyto- plasmic nodes of communication, that `talk' with nuclear-receptor complexes to specify and/or modulate transcriptional responses which determine cell fate. Setting the stage for leukemic hemopoiesis First, let us set the stage on which the drama is played: a chromosomal translocation occurs in a cell that has embarked on a fast-developing maturation program. Hemopoiesis is a developmental process in which a stem cell is progressively modi®ed through distinct short-lived biological programs to give rise to a highly diversi®ed progeny of mature cells. Progenitor renewal, dierentiation, maturation and apoptosis, working in unison, tightly control the size of each cell compart- ment. These processes are regulated by intrinsic cell features and external in¯uences from the hemopoietic Oncogene (2001) 20, 7161 ± 7177 ã 2001 Nature Publishing Group All rights reserved 0950 ± 9232/01 $15.00 www.nature.com/onc *Correspondence: M Lanotte, INSERM U-496, Centre G. Hayem, HoÃpital Saint-Louis, 1, avenue Claude-Vellefaux, 75010 Paris, France; E-mail: mlanotte@chu-stlouis.fr