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Myelodysplasias

Epigenetic regulation of nuclear PI-PLCbeta1 signaling pathway in low-risk MDS patients during azacitidine treatment

Leukemia volume 26, pages 943–950 (2012)Cite this article

Abstract

Phosphoinositide-phospholipase C (PI-PLC) beta1 can be considered a specific target for demethylating therapy in high-risk myelodysplastic syndrome (MDS) patients, as azacitidine treatment has been associated with a PI-PLCbeta1-specific promoter demethylation, and induction of PI-PLCbeta1 gene and protein expression. However, little is known about the molecular effect of azacitidine in low-risk MDS or the functional mechanisms linked with azacitidine effect on PI-PLCbeta1 promoter. In the present study, we further investigated the role of epigenetic regulation of PI-PLCbeta1, mainly focusing on the structure of the PI-PLCbeta1 promoter. We first examined the effect of azacitidine on PI-PLCbeta1 promoter methylation and gene expression in low-risk MDS. Moreover, we studied the expression of key molecules associated with the nuclear inositide signaling pathways, such as cyclin D3. By applying a chromatin immunoprecipitation method, we also studied the correlation between the demethylating effect of azacitidine and the degree of recruitment to PI-PLCbeta1 promoter of some transcription factors implicated in hematopoietic stem cell proliferation and differentiation, as well as of the methyl-CpG-binding domain proteins, which specifically interact with methylated DNA. Taken together, our results hint at a specific involvement of PI-PLCbeta1 in epigenetic mechanisms, and are particularly consistent with the hypothesis of a role for PI-PLCbeta1 in azacitidine-induced myeloid differentiation.

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Acknowledgements

This work was supported by Italian PRIN-Cofin, Italian MIUR-FIRB and Celgene Corporation. We would also thank Dr Emanuela Ottaviani and Dr Mariana Stoyanova from the Department of Hematology and Medical Oncology “L e A Seràgnoli” of the University of Bologna; Dr Anna Candoni and Dr Erika Simeone from the Division of Hematology of the University of Udine; Professor Franco Lauria and Dr Monica Bocchia from the Department of Hematology of the University of Siena; and Dr Maurizio Miglino from the Chair of Hematology of the University of Genova, Italy, for providing biological samples and clinical data.

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Authors and Affiliations

  1. Department of Human Anatomical Sciences, Cellular Signalling Laboratory, University of Bologna, Bologna, Italy

    M Y Follo, S Mongiorgi, L Manzoli, M Piazzi, A M Martelli & L Cocco

  2. Department of Haematology, University of Brescia, Piazzale Spedali Civili 1, Brescia, Italy

    D Russo, C Filì & C Colombi

  3. Institute of Hematology and Medical Oncology “L. e A. Seràgnoli”, University of Bologna, Bologna, Italy

    C Finelli & C Clissa

  4. Department of Clinical Hematology, University of Genova Italy, Genova, Italy

    M Gobbi

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Correspondence to L Cocco.

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Follo, M., Russo, D., Finelli, C. et al. Epigenetic regulation of nuclear PI-PLCbeta1 signaling pathway in low-risk MDS patients during azacitidine treatment. Leukemia 26, 943–950 (2012). https://doi.org/10.1038/leu.2011.300

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