The oncogenic cooperation of TCL1 with T-cell receptor signaling in T-PLL

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T-cell prolymphocytic leukemia (T-PLL) is the most common leukemic mature T-cell lymphoma (MTCL). It is a poor prognostic, yet understudied tumor. Its hallmark is the constitutive transcriptional activation of the T-cell leukemia 1 (TCL1) oncogene. This persistent TCL1 expression in the differentiating peripheral T-cells is considered the initiating event towards T-PLL. However, it is not established how exactly TCL1 acts leukemogenic. Based on initial observations, we proposed that protein-kinase modulation, especially in the context of T-cell receptor (TCR) activation, is a central mechanism. We addressed this by capitalizing on valuable tools established by both PIs: (a) large collections of cell-line systems of defined TCR and TCL1 status and of well-characterized T-PLL samples; (b) autochthonous mouse models of TCL1-driven leukemia mimicking human T-PLL with access to early disease stages; and (c) chimeric antigen receptors (CARs) as engineered TCR mimics allowing interrogations of the importance of defined signaling components. Through the progress in funding phase-I, also involving collaborations with RPs 2-4, we arrived at the following central concept that requires further refinements and validations: T-PLL is a paradigmatic MTCL for a TCR-driven pathogenesis with TCL1 as the central oncogene acting as an enhancer of TCR-signal input through which there is a propensity of accumulating memory-type cells utilizing low-level TCR activation towards transformation. Consequently, we will address in phase-II the detailed mechanisms of the combined action of TCR input and TCL1, the facultative or obligatory relevance of a pro-tumorigenic cooperation of TCL1/TCR signaling at certain phases of leukemic development, the T-cell differentiation stage that is most susceptible to TCL1s in-fluence on TCR signaling, and molecular vulnerabilities that can be deduced for interventional exploitations. In detail, we study in Aim I which TCR/coreceptor components or branches are preferentially impacted by TCL1. Aim II assesses the pro-leukemic cooperation of tonic TCR signaling in the context of overexpressed TCL1 resolved for the exposed T-cell stage vs leukemic phase. In an opposite fashion we will ablate TCR input in Aim III and by that establish the differential necessity of TCR signaling input at early and overt leukemic stages. Finally, in Aim IV we seek to identify molecular targets defined through a specific instruction by TCL1 in the context of TCR signaling that are pharmacologically exploitable for an anti-leukemic potential. The proposed studies will data-feed the competition systems of RP3 and the developing in-silico models on oncogenic modulation of milieu-input triggered intracellular signaling of RP4. Ultimately, by advancing the concepts of TCL1-driven leukemogenesis, our work will also serve to better understand general aspects of perturbed T-cell homeostasis.