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CANCER STEM CELLS |
1 From UF di Ematologia, Dipartimento di Area Critica Medico-Chirurgica, Università degli Studi, Firenze; Istituto Toscano Tumori, Firenze, Italy; on behalf of the MPD-RC, Mount Sinai Hospital, New York, USA.
2 Inserm U602, University Paris-Sud, Villejuif, France
3 Laboratorio di Epidemiologia Clinica, Fondazione IRCCS Policlinico S. Matteo, Pavia
* To whom correspondence should be addressed. E-mail: amvannucchi{at}unifi.it.
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Abstract |
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Constitutive mobilization of CD34+ cells in patients with Primary Myelofibrosis (PMF) has been attributed to proteolytic disruption of CXCR4/SDF-1 axis and reduced CXCR4 expression. We document here that number of circulating CD34+/CXCR4+ cells in PMF patients as well as the cellular CXCR4 expression were directly related to CXCR4 mRNA level, and that reduced CXCR4 mRNA level was not due to SDF-1 induced down-regulation. To address whether epigenetic regulation concurs to defective CXCR4 expression, we studied methylation status of CXCR4 promoter using methylation-specific PCR and methylation-specific sequencing in the JAK2V617F-positive HEL cell line and in CD34+ cells. We found that CD34+ cells from PMF patients, unlike normal subjects, presented hypermethylation of CXCR4 promoter CpG island 1. Following incubation with demethylating agent 5-AzaD the percentage of PMF CD34+ cells expressing CXCR4 increased 3-10 times, while CXCR4 mRNA level raised of about 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 CXCR4 promoter as a mechanism contributing to constitutive migration of CD34+ cells in PMF.
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Author contributions: C.B.: Conception and design, collection and/or assembly of data, data analysis and interpretation; V.P.: Conception and design, collection and/or assembly of data; P.G.: Conception and design, provision of study material or patients, data analysis and interpretation, manuscript writing; C.D.: Collection and/or assembly of data; V.R.: Collection and/or assembly of data; A.B.: Provision of study material or patients; M.L.B.: Data analysis and interpretation, manuscript writing; G.B.: Data analysis and interpretation, manuscript writing; A.M.V.: Conception and design, financial support, provision of study material or patients, data analysis and interpretation, manuscript writing. All authors gave final approval of the manuscript.
Key Words. CXCR4, methylation, myelofibrosis, CD34+ cell, epigenetic
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