Methylation of theIL-12Rβ2Gene as Novel Tumor Escape Mechanism for Pediatric B-Acute Lymphoblastic Leukemia Cells

Open Access
Publisher Website
Google Scholar
Abstract
Previous studies have shown that the interleukin-12 receptor β2 (IL-12Rβ2) 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-12Rβ2 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-12Rβ2 chain. Similarly, primary tumor cells from pediatric pro-B, early pre-B, and pre-B ALL (30 cases) did not express the IL-12Rβ2 chain. IL-12Rβ2 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-12Rβ2 gene. Detection of IL-12Rβ2 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-12Rβ2 gene represents a novel mechanism of tumor escape for B-ALL cells. (Cancer Res 2006; 66(8): 3978-80)