title: The IL-12Rbeta2 gene functions as a tumor suppressor in human B cell malignancies.
abstract: 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.
authors.affiliation: Laboratory of Oncology, G. Gaslini Institute, Genoa, Italy. laboncologia@ospedale-gaslini.ge.it
authors.forename: Irma
authors.initials: I
authors.lastname: Airoldi
authors.forename: Emma
authors.initials: E
authors.lastname: Di Carlo
authors.forename: Barbara
authors.initials: B
authors.lastname: Banelli
authors.forename: Lidia
authors.initials: L
authors.lastname: Moserle
authors.forename: Claudia
authors.initials: C
authors.lastname: Cocco
authors.forename: Annalisa
authors.initials: A
authors.lastname: Pezzolo
authors.forename: Carlo
authors.initials: C
authors.lastname: Sorrentino
authors.forename: Edoardo
authors.initials: E
authors.lastname: Rossi
authors.forename: Massimo
authors.initials: M
authors.lastname: Romani
authors.forename: Alberto
authors.initials: A
authors.lastname: Amadori
authors.forename: Vito
authors.initials: V
authors.lastname: Pistoia
mesh_terms: 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
chemical_list: D018123:Receptors, Interleukin; D053707:Receptors, Interleukin-12; D018664:Interleukin-12; D000077209:Decitabine; D015254:DNA Modification Methylases; D001374:Azacitidine