Methylation of the IL-12Rbeta2 gene as novel tumor escape mechanism for pediatric B-acute lymphoblastic leukemia cells.
Previous studies have shown that the interleukin-12 receptor beta2 (IL-12Rbeta2) 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-12Rbeta2 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-12Rbeta2 chain. Similarly, primary tumor cells from pediatric pro-B, early pre-B, and pre-B ALL (30 cases) did not express the IL-12Rbeta2 chain. IL-12Rbeta2 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-12Rbeta2 gene. Detection of IL-12Rbeta2 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-12Rbeta2 gene represents a novel mechanism of tumor escape for B-ALL cells.
Airoldi
Irma
I
Laboratory of Oncology, G. Gaslini Institute, Genova, Italy. irmaairoldi@ospedale-gaslini.ge.it
Cocco
Claudia
C
Di Carlo
Emma
E
Disarò
Silvia
S
Ognio
Emanuela
E
Basso
Giuseppe
G
Pistoia
Vito
V
D000818:Animals; D018941:Antigens, CD19 / Q000096:biosynthesis / Q000276:immunology; D002051:Burkitt Lymphoma / Q000235:genetics* / Q000276:immunology; D002648:Child; D019175:DNA Methylation; D005260:Female; D020868:Gene Silencing; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018123:Receptors, Interleukin / Q000235:genetics* / Q000276:immunology; D053707:Receptors, Interleukin-12
D018941:Antigens, CD19; C508439:IL12RB2 protein, human; C508443:Il12rb2 protein, mouse; D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12