title: Lack of TIR8/SIGIRR triggers progression of chronic lymphocytic leukemia in mouse models.
abstract: Inflammation is involved in the initiation and progression of several chronic lymphoid malignancies of B-cell type. Toll-like receptors (TLR) are transmembrane inflammatory receptors that on recognition of pathogen-associated molecular patterns trigger an innate immune response and bridge the innate and adaptive immune response by acting as costimulatory signals for B cells. Fine tuning of TLR and IL-1R-like (ILR) activity is regulated by TIR8 (SIGIRR), a transmembrane receptor of the TLR/ILR family which inhibits other family members. To test the hypothesis that TLR and/or ILR may play a role in the natural history of chronic B-cell tumors, we crossed Eμ-TCL1 transgenic mice, a well established model of chronic lymphocytic leukemia (CLL), with mice lacking the inhibitory receptor TIR8 that allow an unabated TLR-mediated stimulation. We here report that in the absence of TIR8 the appearance of monoclonal B-cell expansions is accelerated and mouse life span is shortened. The morphology and phenotype of the mouse leukemic expansions reproduce the progression of human CLL into an aggressive and frequently terminal phase characterized by the appearance of prolymphocytes. This study reveals an important pathogenetic implication of TLR in CLL development and progression.
authors.affiliation: Division of Molecular Oncology, San Raffaele Scientific Institute, Milano, Italy.
authors.forename: Maria Teresa Sabrina
authors.initials: MT
authors.lastname: Bertilaccio
authors.forename: Giorgia
authors.initials: G
authors.lastname: Simonetti
authors.forename: Antonis
authors.initials: A
authors.lastname: Dagklis
authors.forename: Martina
authors.initials: M
authors.lastname: Rocchi
authors.forename: Tania Veliz
authors.initials: TV
authors.lastname: Rodriguez
authors.forename: Benedetta
authors.initials: B
authors.lastname: Apollonio
authors.forename: Alberto
authors.initials: A
authors.lastname: Mantovani
authors.forename: Maurilio
authors.initials: M
authors.lastname: Ponzoni
authors.forename: Paolo
authors.initials: P
authors.lastname: Ghia
authors.forename: Cecilia
authors.initials: C
authors.lastname: Garlanda
authors.forename: Federico
authors.initials: F
authors.lastname: Caligaris-Cappio
authors.forename: Marta
authors.initials: M
authors.lastname: Muzio
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D018956:CD5 Antigens / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology; D017472:Receptors, Interleukin-1 / Q000235:genetics* / Q000276:immunology*; D051193:Toll-Like Receptors / Q000276:immunology
chemical_list: D018941:Antigens, CD19; D018956:CD5 Antigens; D011518:Proto-Oncogene Proteins; D017472:Receptors, Interleukin-1; D051193:Toll-Like Receptors; C526836:Cd5 protein, mouse; C490393:Tcl1 protein, mouse; C484529:SIGIRR protein, mouse