A clonotype-independent pre-TCR complex and its downstream signals can support transformation of thymic T cells.

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Abstract The kinase ataxia telangiectasia mutated (ATM) communicates between molecules that sense DNA damage in the form of double stranded breaks (DSB) and effector mechanisms that maintain genomic integrity. Persistent DSBs can lead to transformation and ATM-deficiency is associated with increased lymphoid malignancies in both humans and mice. ATM-deficient mice exclusively develop thymic T cell lymphomas with high penetrance. We explored the requirement for specific components of the TCR and its signaling pathway for the induction of these thymic lymphomas. We generated multiple strains of ATM-deficient mice in which mature T cell are absent by deletion of CD3ɛ, an invariant component of the pre-TCR complex; by deletion of RAG or TCRβ, in which recombining TCR variable components are deleted; or by deletion of LAT, an important component of pre-TCR and TCR signaling. These strains all showed a similar and severe developmental arrest at thymic DN3. Despite this arrest, mice deficient in RAG or TCRβ, exclusively developed thymic T cell lymphomas. In contrast, mice deficient in CD3ɛ or LAT, developed no or few T cell tumors, respectively, but developed B cell lymphomas. These findings suggest the importance of a clonotype-independent TCR complex and its downstream signals in transformation of T cells. Experiments are in progress to ask if survival of ATMKO T cell lymphomas after transformation is similarly dependent on CD3ɛ and LAT signaling.