Key Points

  • T-PLL cells resemble activated T-lymphocytes with augmented memory-type effector functions including a marked anergy to apoptotic triggers

  • Specific co-opting loss of inhibitory receptors and the overexpressed signal enhancer TCL1A lower thresholds towards permissive TCR input

T-cell prolymphocytic leukemia (T-PLL) is a poor-prognostic neoplasm. Differentiation stage and immune-effector functions of the underlying tumor cell are insufficiently characterized. Constitutive activation of the T-cell-leukemia-1A (TCL1A) oncogene distinguishes the (pre)leukemic cell from regular post-thymic T-cells. We assessed here activation-response patterns of the T-PLL lymphocyte and interrogated the modulatory impact by TCL1A. Immunophenotypic and gene expression profiles revealed a unique spectrum of memory-type differentiation of T-PLL with predominant central-memory stages and frequent non-canonical patterns. Virtually all T-PLL expressed a T-cell receptor (TCR) and/or CD28-coreceptor without overrepresentation of specific TCR-clonotypes. The highly activated leukemic cells also revealed losses of negative-regulatory TCR-coreceptors (e.g. CTLA4). TCR-stimulation of T-PLL cells evoked higher-than-normal cell-cycle transition and profiles of cytokine release that resembled those of normal memory T-cells. More activated phenotypes and higher TCL1A correlated with inferior clinical outcomes. TCL1A was linked to T-PLL's marked resistance to activation- and FAS-induced cell death. Enforced TCL1A enhanced phosho-activation of TCR-kinases, second-messenger generation, and JAK/STAT or NFAT transcriptional responses. This reduced the input thresholds for IL-2 secretion in a sensitizer-like fashion. Mice of TCL1A-initiated protracted T-PLL development resembled such features. When equipped with epitope-defined TCRs or CARs, these Lckpr-hTCL1Atg T-cells gained a leukemogenic growth advantage in scenarios of receptor stimulation. Overall, we propose a model of T-PLL pathogenesis in which TCL1A enhances TCR-signals and drives accumulation of death-resistant memory-type cells that utilize amplified low-level stimulatory input and whose loss of negative coregulators additionally maintains their activated state. Treatment rationales are provided by combined interception in TCR- and survival signaling.

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