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

Despite intensive molecular biology investigations over the past 10 years, and an important breakthrough on how PML-RAR alpha, the fusion protein resu lting from t(15;17), can alter RAR alpha and PML functions, no definitive v iews on how leukemia is generated and by what mechanism(s) the normal pheno type is restored, are yet available. 'Resistances' to pharmacological level s of all-traps-retinoic acid (ATRA) have been observed in experimental in v ivo and in vitro models. In this review, we emphasize the key role played b y signal cross-talk for both normal and neoplastic hemopoiesis. After an ov erview of reported experimental data on APL-cell maturation and apoptosis, we apply our current knowledge on signaling pathways to underline those whi ch might generate signal cross-talks. The design of biological models suita ble to decipher the integration of signal cross-talks at the transcriptiona l level should be our first priority today, to generate some realistic ther apeutic approaches After 'Ten Years of Molecular APL', we still know very l ittle about how the disease develops and how effective medicines work.