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

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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

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B-Lymphocytes
Genes
Neoplasms
Interleukin-12
Gene Silencing
B-Lymphocyte Subsets
Transformed Cell Line
decitabine
Inbred NOD Mouse
CpG Islands
SCID Mice
Burkitt Lymphoma
Lymphoproliferative Disorders
Methyltransferases
Exons
Apoptosis
Gene Expression
Cell Line
Messenger RNA
DNA

ASJC Scopus subject areas

  • Medicine(all)

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

In: Journal of Clinical Investigation, Vol. 113, No. 11, 06.2004, p. 1651-1659.

Research output: Contribution to journalArticle

Airoldi, Irma ; Di Carlo, Emma ; Banelli, Barbara ; Moserle, Lidia ; Cocco, Claudia ; Pezzolo, Annalisa ; Sorrentino, Carlo ; Rossi, Edoardo ; Romani, Massimo ; Amadori, Alberto ; Pistoia, Vito. / The IL-12Rβ2 gene functions as a tumor suppressor in human B cell malignacies. In: Journal of Clinical Investigation. 2004 ; Vol. 113, No. 11. pp. 1651-1659.
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