G. Benoit

RAR‐independent RXR signaling induces t(15;17) leukemia cell maturation

Although retinoic acid receptor alpha (RARα) agonists induce the maturation of t(15;17) acute promyelocytic leukemia (APL) cells, drug treatment also selects leukemic blasts expressing PML–RARα fusion proteins with mutated ligand‐binding domains that no longer respond to all‐trans retinoic acid (ATRA). Here we report a novel RARα‐independent signaling pathway that induces maturation of both ATRA‐sensitive and ATRA‐resistant APL NB4 cells, and does not invoke the ligand‐induced alteration of PML–RARα signaling, stability or compartmentalization. This response involves a cross‐talk between RXR agonists and protein kinase A signaling. Our results indicate the existence of a separate RXR‐dependent maturation pathway that can be activated in the absence of known ligands for RXR heterodimerization partners.

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–RARα, the fusion protein resulting from t(15;17), can alter RARα 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.

Arsenic enhances the activation of Stat1 by interferon gamma leading to synergistic expression of IRF-1.

Arsenic trioxide (As2O3) can induce clinical remission in patients with acute promyelocytic leukemia (APL), including those who have relapsed after treatment with all-trans-retinoic acid (RA). In vitro studies with the APL-derived NB4 cell line showed that As2O3 exerts a dose-dependent dual effect, which induces apoptosis at 1u2009μM, whereas at a lower concentration of 0.1u2009μM, a partial differentiation of APL is observed. In non-APL cells, interferon (IFN) α and 1u2009μM As2O3 act synergistically to induce apoptosis. In this report, we show that in NB4 cells and in two RA-resistant NB4-derived cell lines, NB4-R1 and NB4-R2, IFNα or IFNγ combined with 0.1u2009μM As2O3 lead to an increased maturation effect. Moreover, IFNγ alone is able to differentiate RA-sensitive and -resistant cells with a higher maturation effect on NB4-R2 cells. In contrast, all these cells underwent apoptosis in the presence of the cytokine and a higher concentration of As2O3. IFNγ boosted As2O3-induced apoptosis in APL cells as tested by TUNEL, Annexin V staining and activation of caspase 3. As2O3 differently altered IFN-induced gene products; it downregulated PML/RARα and PML, did not alter PKR and Stat1, and upregulated interferon regulatory family (IRF)-1. Synergism by IFNγ and arsenic on IRF-1 expression is mediated by a composite element in the IRF-1 promoter that includes an IFNγ-activation site (GAS) overlapped by a nonconsensus site for nuclear factor kappa B (NFκB). Arsenic has no effect on NFκB, whereas it enhances the activation of Stat1 by IFNγ in NB4 cells leading to an increase in IRF-1 expression.

Origin and nature of pelvic ureter innervation

Innervation of the pelvic ureter traditionally comes from the pelvic plexus. This innervation is independent: adrenergic and cholinergic. The purpose of this study was to describe more precisely the origin and nature of its innervation (adrenergic, cholinergic, nitrergic, and somatic).