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PI-PLCβ-1 and activated Akt levels are linked to azacitidine responsiveness in high-risk myelodysplastic syndromes

Leukemia volume 22, pages 198–200 (2008)Cite this article

Nuclear lipid metabolism has widely been implicated in cell growth, differentiation and neoplastic transformation. Phosphoinositide-phospholipase C (PI-PLC) β-1 is a key enzyme in nuclear signal transduction, and it is involved in many cellular processes, such as proliferation and differentiation.1 The involvement of PI-PLCβ-1 in hematopoietic differentiation prompted us to investigate the role of this signaling molecule in hematological malignancies, focusing particularly on patients affected by myelodysplastic syndromes (MDS) at higher risk of evolution into acute myeloid leukemia (AML). By using fluorescence in situ hybridization (FISH) analysis, our group demonstrated, in a small number of high-risk MDS patients,2 that subjects bearing a mono-allelic cryptic deletion of the PI-PLCβ-1 gene had a worse clinical outcome, as compared with patients having both alleles. In a subsequent study, it has also been shown that the expression profile of both PI-PLCβ-1a and PI-PLCβ-1b mRNAs, which are the two alternative splicing isoforms of PI-PLCβ-1, is altered in high-risk MDS, as compared to healthy donors.3 Interestingly, MDS cells always expressed higher levels of PI-PLCβ-1b mRNA as compared to PI-PLCβ-1a mRNA; this difference may reflect a specific role of PI-PLCβ-1 in MDS, given that the PI-PLCβ-1a splicing isoform demonstrates both nuclear and cytoplasmatic localization, while PI-PLCβ-1b splicing isoform is localized only in the nucleus. Furthermore, our recent studies demonstrated that not only is Akt specifically phosphorylated in high-risk MDS patients, but also mTOR and its downstream targets are activated,4 affecting cell survival and proliferation of MDS cells.

Azacitidine is a DNA methyltransferase inhibitor currently approved for the treatment of MDS and under experimental evaluation for other hematological malignancies.5 Besides showing response rates of 50–80% in MDS, azacitidine has been reported to have a significant impact on the quality of life and progression into AML.6 Nevertheless, the molecular mechanisms underlying this drug are not completely understood. Low-dose regimens with azacitidine have been assumed to act by reversing the epigenetic silencing of target genes involved in the control of cell growth and differentiation. However, although demethylation of a hypermethylated p15/INK4B gene has been demonstrated in MDS patients treated with demethylating therapy,7 this observation does not necessarily mean that this is the main mechanism of action of the drug in vivo. Moreover, since p15 is unlikely to be the only hypermethylated and silenced gene in MDS, it is important to examine the presence of other targets for demethylating treatment.

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Acknowledgements

This work was supported by CARISBO Foundation, Bologna, Italy and Italian Association for Cancer Research (AIRC)

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Authors and Affiliations

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

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

  2. Institute of Hematology and Medical Oncology ‘L. e A. Seràgnoli’, University of Bologna, Bologna, Italy

    C Finelli, C Bosi, G Martinelli & M Baccarani

  3. Hematology Unit, Ospedale Civile di Piacenza,

    C Bosi

  4. Piacenza, Italy

    C Bosi

  5. Istituto per i Trapianti d'Organo e l'Immunocitologia del C.N.R., Sezione di Bologna c/o I.O.R., Bologna, Italy

    A M Martelli

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  1. M Y Follo
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Correspondence to L Cocco.

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Follo, M., Finelli, C., Bosi, C. et al. PI-PLCβ-1 and activated Akt levels are linked to azacitidine responsiveness in high-risk myelodysplastic syndromes. Leukemia 22, 198–200 (2008). https://doi.org/10.1038/sj.leu.2404855

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