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. 2011 Oct 27;118(17):4635-45.
doi: 10.1182/blood-2010-10-313098. Epub 2011 Aug 30.

The cooperating mutation or "second hit" determines the immunologic visibility toward MYC-induced murine lymphomas

Christian Schuster  1 , Angelika Berger, Maria A Hoelzl, Eva M Putz, Anna Frenzel, Olivia Simma, Nadine Moritz, Andrea Hoelbl, Boris Kovacic, Michael Freissmuth, Mathias Müller, Andreas Villunger, Leonard Müllauer, Ana-Iris Schmatz, Berthold Streubel, Edit Porpaczy, Ulrich Jäger, Dagmar Stoiber, Veronika Sexl
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Free article

The cooperating mutation or "second hit" determines the immunologic visibility toward MYC-induced murine lymphomas

Christian Schuster et al. Blood. .
Free article

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.

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