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

Abstract

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 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 ®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 eective medicines work. Oncogene (2001) 20, 7161 ± 7177.

Re-expression of DNA methylation-silenced CD44 gene in a resistant NB4 cell line: rescue of CD44-dependent cell death by cAMP

“…As we reported earlier, NB4-LR1 cells show defects in this crosstalk and pharmacological cAMP signalling is necessary for retinoid induction of maturation. [14][15][16] At present, little is known about the role of cAMP and its crosstalk with retinoids to induce the maturation and the apoptosis of APL. The mechanisms by which cAMP acts seem to be complex and may involve different signalling pathways and targets, including targeting transcription effectors, such as CREB, CBP300, PML-RARa or RXR receptors by direct or indirect phosphorylation, [18][19][20]49 or changes in nuclear bodies 17,50 or late and indirect re-expression of a large list of genes, 43,51,52 including c-Jun and CD44.…”

“…This is typically the case exemplified in vitro by the ATRA-resistant subclone NB4-LR1 cells, which requires a combined cAMP/ATRA treatment to undergo differentiation and cell death. [14][15][16] The additional defects present in these resistant cells, as well as the molecular mechanism(s) by which cAMP acts to normalize the NB4-LR1 cell phenotype, are still poorly understood, although several proposals supported by independent investigations have been recently forwarded. [17][18][19][20][21] In this study, we demonstrate that there is an altered CD44 gene expression in the ATRA-maturation-resistant NB4-LR1 cells, and characterize the molecular defects behind this lack of CD44 receptor expression as DNA methylation of the CD44 promoter and deacetylation of histones at this locus.…”

E2FBP1/hDril1 modulates cell growth through downregulation of promyelocytic leukemia bodies

“…[9][10][11] These provide a scaffold to harbor several prominent regulatory factors including tumor suppressors, transcriptional regulators, and enzymes for signal transduction, and thereby PML-NBs contribute to multiple mechanisms of cellular control. 8,10,[12][13][14][15][16] While the functional interactions of these components remain unclear, the architecture of PML-NBs seems to be particularly important since its abrogation caused by a chromosomal translocation t(15;17) results in acute promyelocytic leukemia. 8,14,16 In contrast, forced expression of PML, as well as the expression of oncogenic Ras, induces apparent hyperplasis (i.e.…”

“…8,10,[12][13][14][15][16] While the functional interactions of these components remain unclear, the architecture of PML-NBs seems to be particularly important since its abrogation caused by a chromosomal translocation t(15;17) results in acute promyelocytic leukemia. 8,14,16 In contrast, forced expression of PML, as well as the expression of oncogenic Ras, induces apparent hyperplasis (i.e. increase in both size and number) of PML-NBs and subsequent commitment to premature senescence.…”

Arsenic trioxide inhibits ATRA-induced prostaglandin E2 and cyclooxygenase-1 in NB4 cells, a model of acute promyelocytic leukemia

“…Indeed, cAMP is well known to synergize with retinoic acid to trigger differentiation in several cell types, including APL cells. 34,35 Recently, Kamashev et al 36 showed that cAMP restored both retinoic acid-triggered differentiation and PML-RARA transcriptional activation in mutant retinoic acid-resistant APL cells. They also demonstrated that APL cell differentiation parallels transcriptional activation through PML-RARA-RXR oligomers and that those are functionally targeted by cAMP, identifying this agent as another oncogene-targeted therapy.…”