The IL-12Rβ2 gene functions as a tumor suppressor in human B cell malignancies
Irma Airoldi, … , Alberto Amadori, Vito Pistoia
Irma Airoldi, … , Alberto Amadori, Vito Pistoia
Published June 1, 2004
Citation Information: J Clin Invest. 2004;113(11):1651-1659. https://doi.org/10.1172/JCI20303.
View: Text | PDF | Retraction
Article Oncology Article has an altmetric score of 1

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

×

Figure 7

Options: View larger image (or click on image) Download as PowerPoint
Tumorigenicity of IL-12Rβ2_transfected Raji cells in SCID-NOD mice. (A) ...
Tumorigenicity of IL-12Rβ2_transfected Raji cells in SCID-NOD mice. (A) The mean size ± SD of tumors formed by IL-12Rβ2_transfected Raji cells in SCID-NOD mice treated with hrIL-12 (black bar) or PBS (gray bar) is shown. The difference between mean size of tumors from hrIL-12 treated and PBS treated mice was statistically significant (P < 0.0001). (B) Two representative tumors grown in hrIL-12_treated and PBS-treated mice are shown. (C) Histological and immunohistochemical features of tumors from PBS treated (C, G, E, and I) and hrIL-12 treated (D, F, H, and J) SCID/NOD mice. IL-12Rβ2 gene_transfected Raji tumors from PBS-treated mice are formed by medium- to large-sized neoplastic cells with round to oval nuclei showing two or more nucleoli. The “starry sky” pattern determined by macrophages that have ingested apoptotic tumor cells is also present (arrows) (C). The tumor is well vascularized (E) and does not express detectable level of Mig/CXCL9 (G). An extremely high proliferation rate is evidenced by Ki-67 immunostaining (I). In tumors from hrIL-12 treated mice the above described architectural features are altered by frequent and extensive areas of ischemic-hemorrhagic necrosis (N) (D), which are associated with defective intratumoral microvessel network (F), and expression of Mig/CXCL9 in the cytoplasm and in the proximity of intact tumor cells (H). In addition, the number of proliferating cells in the viable neoplastic tissue surrounding necrotic areas, as assessed by Ki-67 staining, is strongly reduced (J). Magnification, ∞400, for all pictures shown.