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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Expression of IL-12R in human tonsil B cells. (A) Expression of IL-12Rβ1...
Expression of IL-12R in human tonsil B cells. (A) Expression of IL-12Rβ1 and IL-12Rβ2 mRNA in tonsil B cells and their subsets. From left to right: molecular weight markers (MW); negative control (NC, represented by a Th2 cell clone for CD56, CD19, and IL-12Rβ2 primers; purified tonsil B cells for CD3γ primers; or water in the place of cDNA for IL12Rβ1 and GAPDH primers); positive control (PC, represented by a Th1 cell clone for CD3γ, IL12Rβ1, and IL-12Rβ2 primers; tonsil non_T cells for CD56 primers; or the RPMI 8866 B cell line for CD19 primers). The remaining lanes represent total tonsil B lymphocytes and naive, GC, and memory B cells, respectively, isolated from the same tonsil. On the right, the expected molecular weight of the amplified bands are shown. (B_N) Expression of IL-12Rβ2 protein in frozen tonsil tissue sections. (B) FM, GC, and SE, are boxed (magnification, ∞20). FM staining with CD19 mAb (C, green), anti_IL-12Rβ2 mAb (D, red), and both mAb's in combination with DAPI (E); in E, overlap of green and red colors gives rise to yellow staining, indicating that most cells coexpress CD19 and IL-12Rβ2; control FM staining with DAPI and with isotype- and fluorochrome-matched mAb's of irrelevant specificity (F). Staining of SEs (G_J) and GC areas (K_N) are shown in the same order as FM. Magnification (C_N), ∞100 for all panels.