Oberbeck, S., Schrader, A., Warner, K., Jungherz, D., Crispatzu, G., von Jan, J., Chmielewski, M., Ianevski, A., Diebner, H. H., Mayer, P., Ados, A. Kondo, Wahnschaffe, L., Braun, T., Mueller, T. A., Wagle, P., Bouska, A., Neumann, T., Puetzer, S., Varghese, L., Pflug, N., Thelen, M., Makalowski, J., Riet, N., Goex, H. J. M., Rappl, G., Altmueller, J., Kotrova, M., Persigehl, T., Hopfinger, G., Hansmann, M. L., Schloesser, H., Stilgenbauer, S., Duerig, J., Mougiakakos, D., Von Bergwelt-Baildon, M., Roeder, I, Hartmann, S., Hallek, M., Moriggl, R., Brueggemann, M., Aittokallio, T., Iqbal, J., Newrzela, S., Abken, H. and 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). S. 2786 - 2803. WASHINGTON: AMER SOC HEMATOLOGY. ISSN 1528-0020

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Oberbeck, S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schrader, A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Warner, K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jungherz, D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Crispatzu, G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
von Jan, J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chmielewski, M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ianevski, A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Diebner, H. H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mayer, P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ados, A. KondoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wahnschaffe, L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Braun, T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mueller, T. A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wagle, P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bouska, A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neumann, T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Puetzer, S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Varghese, L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pflug, N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thelen, M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Makalowski, J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Riet, N.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Goex, H. J. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rappl, G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kotrova, M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Persigehl, T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hopfinger, G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hansmann, M. L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schloesser, H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stilgenbauer, S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Duerig, J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mougiakakos, D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Von Bergwelt-Baildon, M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Roeder, IUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hartmann, S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hallek, M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moriggl, R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brueggemann, M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aittokallio, T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Iqbal, J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Newrzela, S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Abken, H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herling, M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-308343
DOI: 10.1182/blood.2019003348
Journal or Publication Title: Blood
Volume: 136
Number: 24
Page Range: S. 2786 - 2803
Date: 2020
Publisher: AMER SOC HEMATOLOGY
Place of Publication: WASHINGTON
ISSN: 1528-0020
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
PROLYMPHOCYTIC LEUKEMIA; EXPRESSION; LYMPHOMA; DIFFERENTIATION; IDENTIFICATION; PATTERNSMultiple languages
HematologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/30834

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