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Methylation of the IL-12Rß2 Gene as Novel Tumor Escape Mechanism for Pediatric B-Acute Lymphoblastic Leukemia Cells

¹ Laboratory of Oncology, G. Gaslini Institute; ² Animal Model Facility, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy; ³ Department of Oncology and Neurosciences and Center of Excellence on Aging, G. D'Annunzio University, Chieti, Italy; and ⁴ Division of Hematology Oncology, Department of Pediatrics, University of Padova, Padova, Italy

Requests for reprints: Irma Airoldi, Laboratory of Oncology, G. Gaslini Institute, Largo G. Gaslini 5, 16148 Genova, Italy. Phone: 39-10-5636342; Fax: 39-10-3779820; E-mail: irmaairoldi{at}ospedale-gaslini.ge.it.

Previous studies have shown that the interleukin-12 receptor ß2 (IL-12Rß2) gene is expressed in normal naive, germinal center and memory B cells but not in their malignant counterparts. The aim of this study was to investigate (i) whether the IL-12Rß2 gene is silenced in B-cell acute lymphoblastic leukemia (B-ALL) cells, and (ii) what the functional implications of such silencing for tumor growth are. Here, we show that although mature B cells expressed both chains of the IL-12R, normal pro-B and pre-B cells failed to express the IL-12Rß2 chain. Similarly, primary tumor cells from pediatric pro-B, early pre-B, and pre-B ALL (30 cases) did not express the IL-12Rß2 chain. IL-12Rß2 gene silencing in B-ALL was found to depend on methylation of a CpG island in exon 1. Such methylation was not detected in normal early B cells that when differentiated into mature B cells expressed the IL-12Rß2 gene. Detection of IL-12Rß2 mRNA and protein in the tumorigenic 697 pre-B-ALL cell line allowed to perform functional experiments in severe combined immunodeficient/nonobese diabetic mice receiving 697 cells with or without human recombinant IL-12 (hrIL-12). hrIL-12 administration reduced tumor growth and metastasis through antiproliferative and proapoptotic rather than antiangiogenic, activities.

In conclusion, epigenetic silencing of the IL-12Rß2 gene represents a novel mechanism of tumor escape for B-ALL cells. (Cancer Res 2006; 66(8): 3978-80)

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