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-RARalpha, the fusion protein resulting from t(15;17), can alter RARalpha and PML functions, no definitive 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 knowledge 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 first 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 effective medicines work.
Benoit
G
G
INSERM U-496, Hôpital Saint-Louis, 1, avenue Claude-Vellefaux, 75010 Paris, France.
Roussel
M
M
Pendino
F
F
Ségal-Bendirdjian
E
E
Lanotte
M
M
D017209:Apoptosis; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D018450:Disease Progression; D006410:Hematopoiesis; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D009363:Neoplasm Proteins / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000378:metabolism; D020239:Receptor Cross-Talk; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D047488:Retinoid X Receptors; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors / Q000378:metabolism; D014178:Translocation, Genetic
D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein