The IL-12Rβ2 gene functions as a tumor suppressor in human B cell malignancies
Irma Airoldi, Emma Di Carlo, Barbara Banelli, Lidia Moserle, Claudia Cocco, Annalisa Pezzolo, Carlo Sorrentino, Edoardo Rossi, Massimo Romani, Alberto Amadori, Vito Pistoia
Irma Airoldi, Emma Di Carlo, Barbara Banelli, Lidia Moserle, Claudia Cocco, Annalisa Pezzolo, Carlo Sorrentino, Edoardo Rossi, Massimo Romani, Alberto Amadori, Vito Pistoia
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Article Oncology

The IL-12Rβ2 gene functions as a tumor suppressor in human B cell malignancies

Abstract

The IL-12Rβ2 gene is expressed in human mature B cell subsets but not in transformed B cell lines. Silencing of this gene may be advantageous to neoplastic B cells. Our objective was to investigate the mechanism(s) and the functional consequence(s) of IL-12Rβ2 gene silencing in primary B cell tumors and transformed B cell lines. Purified tumor cells from 41 patients with different chronic B cell lymphoproliferative disorders, representing the counterparts of the major mature human B cell subsets, tested negative for IL-12Rβ2 gene expression. Hypermethylation of a CpG island in the noncoding exon 1 was associated with silencing of this gene in malignant B cells. Treatment with the DNA methyltransferase inhibitor 5-Aza-2′-deoxycytidine restored IL-12Rβ2 mRNA expression in primary neoplastic B cells that underwent apoptosis following exposure to human recombinant IL-12 (hrIL-12). hrIL-12 inhibited proliferation and increased the apoptotic rate of IL-12Rβ2–transfected B cell lines in vitro. Finally, hrIL-12 strongly reduced the tumorigenicity of IL-12Rβ2–transfected Burkitt lymphoma RAJI cells in SCID-NOD mice through antiproliferative and proapoptotic effects, coupled with neoangiogenesis inhibition related to human IFN-γ–independent induction of hMig/CXCL9. The IL-12Rβ2 gene acts as tumor suppressor in chronic B cell malignancies, and IL-12 exerts direct antitumor effects on IL-12Rβ2–expressing neoplastic B cells.

Authors

Irma Airoldi, Emma Di Carlo, Barbara Banelli, Lidia Moserle, Claudia Cocco, Annalisa Pezzolo, Carlo Sorrentino, Edoardo Rossi, Massimo Romani, Alberto Amadori, Vito Pistoia

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Induction of IL-12Rβ2 by treatment with 5-Aza-2′-deoxycytidine in primar...
Induction of IL-12Rβ2 by treatment with 5-Aza-2′-deoxycytidine in primary tumors. (A) Left panel: Freshly isolated B-CLL cells (T0), B-CLL cells cultured with medium alone (medium) or in the presence of 5 ∝M 5-Aza-2′-deoxycytidine (Aza) for 48 to 96 hours. One sample representative of the four tested is shown. Right panel. Purified FL cells cultured with medium alone (medium) or in the presence of 5-Aza-2′-deoxycytidine for 72h. One sample representative of the two tested is shown. (B) Apoptosis of primary neoplastic B cells incubated with 5-Aza-2′-deoxycytidine for 72 hours and subsequently cultured with hrIL-12 for an additional 48 hours, as assessed by the TUNEL assay. Histogram in the left panel shows the percentages of apoptotic cells detected following culture with medium alone (white bar); with 5-Aza-2′-deoxycytidine for 72 hours and subsequently with medium for additional 48 hours (gray bar); or with 5-Aza-2′-deoxycytidine for 72 hours and subsequently with hrIL-12 for an additional 48 hours (black bar, Aza + IL-12). Two B-CLL and 2 FL samples are shown. In the right panel, one representative experiment performed with B-CLL1 sample is shown. TUNEL positive nuclei stained with FITC are green, whereas interphase nuclei stained with DAPI are blue (magnification, ∞20).