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

Autor:	Oberbeck S; Department I of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf.; CECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, and.; Center for Molecular Medicine Cologne, University of Cologne (UoC), Cologne, Germany., Schrader A; Department I of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf.; CECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, and.; Center for Molecular Medicine Cologne, University of Cologne (UoC), Cologne, Germany., Warner K; Department I of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf.; Senckenberg Institute of Pathology, Goethe University, Frankfurt am Main, Germany., Jungherz D; Department I of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf.; CECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, and.; Center for Molecular Medicine Cologne, University of Cologne (UoC), Cologne, Germany., Crispatzu G; Department I of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf.; CECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, and.; Center for Molecular Medicine Cologne, University of Cologne (UoC), Cologne, Germany., von Jan J; Department I of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf.; CECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, and.; Center for Molecular Medicine Cologne, University of Cologne (UoC), Cologne, Germany., Chmielewski M; Department I of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf.; CECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, and.; Center for Molecular Medicine Cologne, University of Cologne (UoC), Cologne, Germany., Ianevski A; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland., Diebner HH; Faculty of Medicine Carl Gustav Carus, Institute for Medical Informatics and Biometry Dresden, Technische Universität Dresden, Dresden, Germany., Mayer P; Department I of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf.; CECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, and.; Center for Molecular Medicine Cologne, University of Cologne (UoC), Cologne, Germany., Kondo Ados A; Department I of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf.; CECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, and.; Center for Molecular Medicine Cologne, University of Cologne (UoC), Cologne, Germany., Wahnschaffe L; Department I of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf.; CECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, and.; Center for Molecular Medicine Cologne, University of Cologne (UoC), Cologne, Germany., Braun T; Department I of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf.; CECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, and.; Center for Molecular Medicine Cologne, University of Cologne (UoC), Cologne, Germany., Müller TA; Department I of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf.; CECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, and.; Center for Molecular Medicine Cologne, University of Cologne (UoC), Cologne, Germany., Wagle P; CECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, and., Bouska A; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE., Neumann T; Department I of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf.; CECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, and.; Center for Molecular Medicine Cologne, University of Cologne (UoC), Cologne, Germany., Pützer S; Department I of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf.; CECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, and.; Center for Molecular Medicine Cologne, University of Cologne (UoC), Cologne, Germany., Varghese L; Department I of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf.; CECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, and.; Center for Molecular Medicine Cologne, University of Cologne (UoC), Cologne, Germany., Pflug N; Department I of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf., Thelen M; Department I of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf.; Center for Molecular Medicine Cologne, University of Cologne (UoC), Cologne, Germany., Makalowski J; Department I of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf.; Center for Molecular Medicine Cologne, University of Cologne (UoC), Cologne, Germany., Riet N; Department I of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf.; Center for Molecular Medicine Cologne, University of Cologne (UoC), Cologne, Germany., Göx HJM; Department I of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf.; CECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, and., Rappl G; Department I of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf.; Center for Molecular Medicine Cologne, University of Cologne (UoC), Cologne, Germany., Altmüller J; Cologne Center for Genomics, Institute of Human Genetics, UoC, Cologne, Germany., Kotrová M; Medical Department II of Hematology and Oncology, University Hospital of Schleswig Holstein, Campus Kiel, Kiel, Germany., Persigehl T; Department of Radiology, UoC, Cologne, Germany., Hopfinger G; Center for Oncology and Hematology, Kaiser-Franz-Josef-Spital, Vienna, Austria., Hansmann ML; Senckenberg Institute of Pathology, Goethe University, Frankfurt am Main, Germany., Schlößer H; Center for Molecular Medicine Cologne, University of Cologne (UoC), Cologne, Germany., Stilgenbauer S; Department III of Internal Medicine, University Hospital Ulm, Ulm, Germany., Dürig J; Clinic for Hematology, University Hospital Essen, Essen, Germany., Mougiakakos D; Department of Medicine 5, Hematology, and Oncology, University Hospital Erlangen, Erlangen, Germany., von Bergwelt-Baildon M; Department of Medicine III, University Hospital LMU Munich, Munich, Germany., Roeder I; Faculty of Medicine Carl Gustav Carus, Institute for Medical Informatics and Biometry Dresden, Technische Universität Dresden, Dresden, Germany., Hartmann S; Senckenberg Institute of Pathology, Goethe University, Frankfurt am Main, Germany., Hallek M; Department I of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf.; CECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, and.; Center for Molecular Medicine Cologne, University of Cologne (UoC), Cologne, Germany., Moriggl R; Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Vienna, Austria.; Ludwig Boltzmann Institute for Cancer Research, Medical University of Vienna, Vienna, Austria; and., Brüggemann M; Medical Department II of Hematology and Oncology, University Hospital of Schleswig Holstein, Campus Kiel, Kiel, Germany., Aittokallio T; Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland., Iqbal J; Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE., Newrzela S; Senckenberg Institute of Pathology, Goethe University, Frankfurt am Main, Germany., Abken H; RCI Regensburg Center for Interventional Immunology, Regensburg, Germany., Herling M; Department I of Internal Medicine, Center for Integrated Oncology Aachen-Bonn-Cologne-Duesseldorf.; CECAD Center of Excellence on Cellular Stress Responses in Aging-Associated Diseases, and.; Center for Molecular Medicine Cologne, University of Cologne (UoC), Cologne, Germany.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2020 Dec 10; Vol. 136 (24), pp. 2786-2802.
DOI:	10.1182/blood.2019003348
Abstrakt:	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 activation- and 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-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 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. (© 2020 by The American Society of Hematology.)
Databáze:	MEDLINE
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