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Chronic Lymphocytic Leukemia

Post-transcriptional regulation of inducible nitric oxide synthase in chronic lymphocytic leukemia B cells in pro- and antiapoptotic culture conditions

Leukemia volume 18, pages 48–56 (2004)Cite this article

Abstract

Functional inducible NOS (iNOS) may be involved in the prolonged lifespan of chronic lymphocytic leukemia cells (B-CLL), although the exact mechanisms implicated remain elusive as yet. In this work, we have examined iNOS expression in normal B lymphocytes and B-CLL cells in pro- and antiapoptotic conditions. Our results demonstrate: (1) The existence of a new splice variant characterized by a complete deletion of exon 14 (iNOS 13–1614del), which was preferentially detected in normal B lymphocytes and may represent an isoform that could play a role in the regulation of enzyme activity. (2) The existence of another alternatively spliced iNOS mRNA transcript involving a partial deletion of the flavodoxin region (iNOS 13–16neg) was correlated to a decreased B-CLL cell viability. The 9-β-D-arabinofuranosyl-2-fluoradenine or fludarabine (F-ara) treatment induced iNOS 13–16neg transcript variants, whereas IL-4 enhanced both the transcription of variants, including these exons (iNOS 13–16pos), and the expression of a 122 kDa iNOS protein. These results suggest that in B-CLL, a regulation process involving nitric oxide (•NO) levels could occur by a post-transcriptional mechanism mediated by soluble factors. Our results also provide an insight into a new complementary proapoptotic action of F-ara in B-CLL by the induction of particular iNOS splice variants, leading to the activation of a caspase-3-dependent apoptotic pathway.

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Acknowledgements

This work was supported in part by grants from Comisión Honoraria de Lucha contra el Cáncer, CSIC (Universidad de la República, Uruguay), Schering Uruguaya and Fundación Manuel Pérez. We thank Rafael Radi, Sergio Bianchi, Nicolás Arrambide, Gerard Dumas and Yuri Vasconcelos for critical discussion.

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Authors and Affiliations

  1. Departamento de Bioquímica, de la Facultad de Medicina, Universidad de la República, Montevideo, Uruguay

    A C Tiscornia, C Brito, C Robello & O Pritsch

  2. Departamento de Básico de Medicina, de la Facultad de Medicina, Universidad de la República, Montevideo, Uruguay

    A Cayota

  3. Servicio de Hematología y Transplante de Médula Ósea, Hospital Maciel, Montevideo, Uruguay

    A I Landoni & R Gabús

  4. Unité d' Immunohématologie, Institut Pasteur, Paris, France

    P Oppezzo, F Vuillier & G Dighiero

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Tiscornia, A., Cayota, A., Landoni, A. et al. Post-transcriptional regulation of inducible nitric oxide synthase in chronic lymphocytic leukemia B cells in pro- and antiapoptotic culture conditions. Leukemia 18, 48–56 (2004). https://doi.org/10.1038/sj.leu.2403169

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