Originally published as JCO Early Release 10.1200/JCO.2008.19.3748 on December 29 2008

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Phosphoinositide-Phospholipase C β1 Mono-Allelic Deletion Is Associated With Myelodysplastic Syndromes Evolution Into Acute Myeloid Leukemia

From the Cellular Signalling Laboratory, Department of Human Anatomical Sciences; Institute of Hematology and Medical Oncology "L. e A. Seràgnoli", University of Bologna; Hematology Unit, Ospedale Civile di Piacenza; and the Istituto per i Trapianti d'Organo e l'Immunocitologia del CNR, Sezione di Bologna, Bologna, Italy.

Corresponding author: Lucio Cocco, MD, Cellular Signalling Laboratory, Department of Human Anatomical Sciences, University of Bologna, via Irnerio 48, 40126 Bologna, Italy; e-mail: lucio.cocco{at}unibo.it.

Purpose To evaluate the association between the presence of phosphoinositide-phospholipase C β1 (PI-PLCβ1) mono-allelic deletion with the clinical outcome of myelodysplastic syndromes (MDS) patients.

Methods PI-PLCβ1, PI-PLCβ4, and PI-PLC1 cytogenetic investigations were performed on 80 newly diagnosed MDS patients (18 low risk, 26 intermediate 1, 18 intermediate 2, 18 high risk) comparing the results with the clinical outcome of the patients. Moreover, fluorescent in situ hybridization results were validated by real-time polymerase chain reaction (PCR). Finally, PI-PLCβ1 gene and protein expression were assessed by both real-time PCR and immunocytochemical experiments.

Results Collectively, 35 (43.75%) of 80 of the MDS patients showed a specific mono-allelic deletion of PI-PLCβ1. Kaplan-Meier analysis revealed a significant association (P < .0001) between the PI-PLCβ1 mono-allelic deletion and a higher risk of evolution into acute myeloid leukemia (AML), since 23 of 35 MDS patients (65.7%) bearing the PI-PLCβ1 mono-allelic deletion evolved into AML. Even in multivariate analysis, the PI-PLCβ1 mono-allelic deletion retained a higher significance, with a P < .001, as a prognostic factor of evolution into AML (odds ratio [OR] 1.83; 95% CI, 2.26 to 17.24; P = .00045). Finally, PI-PLCβ1 deletion was related to an altered gene and protein expression.

Conclusion PI-PLCβ1 mono-allelic deletion is associated with a worse clinical outcome in MDS patients, hinting at the identification of a new group at higher risk of AML evolution and representing a reliable prognostic tool. Moreover, targeting PI-PLCβ1 pathways might emerge as a new therapeutic strategy for MDS.

Supported by Italian MIUR-FIRB Human Proteome Net and by CARISBO Foundation, Bologna, Italy.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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