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Noncanonical effector functions of the T-memory-like T-PLL cell are shaped by cooperative TCL1A and TCR signaling

Oberbeck S, Schrader A, Warner K, Jungherz D, Crispatzu G, Von Jan J, Chmielewski M, Ianevski A, Diebner HH, Mayer P, Ados AK, Wahnschaffe L, Braun T, Mueller TA, Wagle P, Bouska A, Neumann T, Puetzer S, Varghese L, Pflug N, Thelen M, Makalowski J, Riet N, Goex HJM, Rappl G, Altmueller J, Kotrova M, Persigehl T, Hopfinger G, Hansmann ML, Schloesser H, Stilgenbauer S, Duerig J, Mougiakakos D, Von Bergwelt-Baildon M, Roeder , Hartmann S, Hallek M, Moriggl R, Brueggemann M, Aittokallio T, Iqbal J, Newrzela S, Abken H, Herling M (2020)

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Publication Type: Journal article

Publication year: 2020

Journal

Book Volume: 136

Pages Range: 2786-2802

Journal Issue: 24

DOI: 10.1182/blood.2019003348

Abstract

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 postthymic T cells. We assessed 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 noncanonical 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 (eg, 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 the marked resistance of T-PLL to activationand FAS-induced cell death. Enforced TCL1A enhanced phospho-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 chimeric antigen receptors, these Lckpr-hTCL1AtgT 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 the accumulation of death-resistant memory-type cells that use 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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APA:

Oberbeck, S., Schrader, A., Warner, K., Jungherz, D., Crispatzu, G., Von Jan, J.,... Herling, M. (2020). Noncanonical effector functions of the T-memory-like T-PLL cell are shaped by cooperative TCL1A and TCR signaling. Blood, 136(24), 2786-2802. https://doi.org/10.1182/blood.2019003348

MLA:

Oberbeck, S., et al. "Noncanonical effector functions of the T-memory-like T-PLL cell are shaped by cooperative TCL1A and TCR signaling." Blood 136.24 (2020): 2786-2802.

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