The IL-12Rbeta2 gene functions as a tumor suppressor in human B cell malignancies.
The IL-12Rbeta2 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-12Rbeta2 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-12Rbeta2 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-12Rbeta2 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-12Rbeta2-transfected B cell lines in vitro. Finally, hrIL-12 strongly reduced the tumorigenicity of IL-12Rbeta2-transfected Burkitt lymphoma RAJI cells in SCID-NOD mice through antiproliferative and proapoptotic effects, coupled with neoangiogenesis inhibition related to human IFN-gamma-independent induction of hMig/CXCL9. The IL-12Rbeta2 gene acts as tumor suppressor in chronic B cell malignancies, and IL-12 exerts direct antitumor effects on IL-12Rbeta2-expressing neoplastic B cells.
Airoldi
Irma
I
Laboratory of Oncology, G. Gaslini Institute, Genoa, Italy. laboncologia@ospedale-gaslini.ge.it
Di Carlo
Emma
E
Banelli
Barbara
B
Moserle
Lidia
L
Cocco
Claudia
C
Pezzolo
Annalisa
A
Sorrentino
Carlo
C
Rossi
Edoardo
E
Romani
Massimo
M
Amadori
Alberto
A
Pistoia
Vito
V
D000818:Animals; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001402:B-Lymphocytes / Q000378:metabolism; D002908:Chronic Disease; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors; D000077209:Decitabine; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D006801:Humans; D018664:Interleukin-12 / Q000378:metabolism; D015448:Leukemia, B-Cell / Q000235:genetics* / Q000378:metabolism; D008232:Lymphoproliferative Disorders / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014066:Palatine Tonsil / Q000166:cytology / Q000378:metabolism; D018123:Receptors, Interleukin / Q000235:genetics* / Q000378:metabolism; D053707:Receptors, Interleukin-12
D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D018664:Interleukin-12; D000077209:Decitabine; D015254:DNA Modification Methylases; D001374:Azacitidine