title: The cooperating mutation or "second hit" determines the immunologic visibility toward MYC-induced murine lymphomas.
abstract: In Eμ-myc transgenic animals lymphoma formation requires additional genetic alterations, which frequently comprise loss of p53 or overexpression of BCL-2. We describe that the nature of the "second hit" affects the ability of the immune system to contain lymphoma development. Tumors with disrupted p53 signaling killed the host more rapidly than BCL-2 overexpressing ones. Relaxing immunologic control, using Tyk2(-/-) mice or by Ab-mediated depletion of CD8(+) T or natural killer (NK) cells accelerated formation of BCL-2-overexpressing lymphomas but not of those lacking p53. Most strikingly, enforced expression of BCL-2 prolonged disease latency in the absence of p53, whereas blocking p53 function in BCL-2-overexpressing tumors failed to accelerate disease. This shows that blocking apoptosis in p53-deficient cells by enforcing BCL-2 expression can mitigate disease progression increasing the "immunologic visibility." In vitro cytotoxicity assays confirmed that high expression of BCL-2 protein facilitates NK and T cell-mediated killing. Moreover, we found that high BCL-2 expression is accompanied by significantly increased levels of the NKG2D ligand MULT1, which may account for the enhanced killing. Our findings provide first evidence that the nature of the second hit affects tumor immunosurveillance in c-MYC-driven lymphomas and define a potential shortcoming of antitumor therapies targeting BCL-2.
authors: Center for Pharmacology and Physiology, Medical University of Vienna, Vienna, Austria.
authors: Christian
authors: C
authors: Schuster
authors: Angelika
authors: A
authors: Berger
authors: Maria A
authors: MA
authors: Hoelzl
authors: Eva M
authors: EM
authors: Putz
authors: Anna
authors: A
authors: Frenzel
authors: Olivia
authors: O
authors: Simma
authors: Nadine
authors: N
authors: Moritz
authors: Andrea
authors: A
authors: Hoelbl
authors: Boris
authors: B
authors: Kovacic
authors: Michael
authors: M
authors: Freissmuth
authors: Mathias
authors: M
authors: Müller
authors: Andreas
authors: A
authors: Villunger
authors: Leonard
authors: L
authors: Müllauer
authors: Ana-Iris
authors: AI
authors: Schmatz
authors: Berthold
authors: B
authors: Streubel
authors: Edit
authors: E
authors: Porpaczy
authors: Ulrich
authors: U
authors: Jäger
authors: Dagmar
authors: D
authors: Stoiber
authors: Veronika
authors: V
authors: Sexl
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D018450:Disease Progression; D004843:Epistasis, Genetic / Q000276:immunology* / Q000502:physiology; D019254:Genes, bcl-2 / Q000502:physiology; D016259:Genes, myc / Q000502:physiology*; D016158:Genes, p53 / Q000502:physiology; D007157:Immunologic Surveillance / Q000235:genetics*; D008223:Lymphoma / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000502:physiology*; D053634:TYK2 Kinase / Q000235:genetics; D019139:Tumor Escape / Q000235:genetics
chemical_list: D053634:TYK2 Kinase; C499356:Tyk2 protein, mouse