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

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

Research output: Contribution to journalArticle

Abstract

The IL-12Rβ2 gene is expressed in human mature B cell subsets but not in transformed B cell lines. Silencing of this gene maybe 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-J2R;beta;2-transfected B cell lines in vitro. Finally, hrIL-12 strongly reduced the tumorigenicity of IL-12β2-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-12β2-expressing neoplastic B cells.

Original languageEnglish
Pages (from-to)1651-1659
Number of pages9
JournalJournal of Clinical Investigation
Volume113
Issue number11
DOIs
Publication statusPublished - Jun 2004

ASJC Scopus subject areas

  • Medicine(all)

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    Airoldi, I., Di Carlo, E., Banelli, B., Moserle, L., Cocco, C., Pezzolo, A., Sorrentino, C., Rossi, E., Romani, M., Amadori, A., & Pistoia, V. (2004). The IL-12Rβ2 gene functions as a tumor suppressor in human B cell malignacies. Journal of Clinical Investigation, 113(11), 1651-1659. https://doi.org/10.1172/JCI200420303