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CANCER STEM CELLS

Hypermethylation of CXCR4 Promoter in CD34⁺ Cells from Patients with Primary Myelofibrosis

^aUnitá Funzionale di Ematologia, Dipartimento di Area Critica Medico-Chirurgica, Università degli Studi, Firenze, Italy;
^bIstituto Toscano Tumori, Firenze, Italy, on behalf of the MPD-RC, Mount Sinai Hospital, New York, New York, USA;
^cInserm U602, University Paris-Sud, Villejuif, France;
^dLaboratorio di Epidemiologia Clinica, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Policlinico S. Matteo, Pavia, Italy

Key Words. CXCR4 • Methylation • Myelofibrosis • CD34+ cell • Epigenetic

Correspondence: Alessandro M. Vannucchi, M.D., Department of Hematology, University of Florence, 50134 Florence, Italy. Telephone: 39-055-7947-688; Fax: 39-055-7947-688; e-mail: amvannucchi{at}unifi.it

Received April 15, 2008; accepted for publication May 15, 2008.
First published online in STEM CELLS EXPRESS   May 29, 2008.

Constitutive mobilization of CD34⁺ cells in patients with primary myelofibrosis (PMF) has been attributed to proteolytic disruption of the CXCR4/SDF-1 axis and reduced CXCR4 expression. We document here that the number of circulating CD34⁺/CXCR4⁺ cells in PMF patients, as well as the cellular CXCR4 expression, was directly related to CXCR4 mRNA level and that reduced CXCR4 mRNA level was not due to SDF-1-induced downregulation. To address whether epigenetic regulation contributes to defective CXCR4 expression, we studied the methylation status of the CXCR4 promoter using methylation-specific polymerase chain reaction and methylation-specific sequencing in the JAK2V617F-positive HEL cell line and in CD34⁺ cells. We found that CD34⁺ cells from PMF patients, unlike those from normal subjects, presented hypermethylation of CXCR4 promoter CpG island 1. Following incubation with the demethylating agent 5-Aza-2'-deoxycytidine (5-AzaD), the percentage of PMF CD34⁺ cells expressing CXCR4 increased 3–10 times, whereas CXCR4 mRNA level increased approximately 4 times. 5-AzaD-treated PMF CD34⁺ cells displayed almost complete reversal of CpG1 island 1 hypermethylation and showed enhanced migration in vitro in response to SDF-1. These data point to abnormal methylation of the CXCR4 promoter as a mechanism contributing to constitutive migration of CD34⁺ cells in PMF.

Disclosure of potential conflicts of interest is found at the end of this article.

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