![[feed]](/style/images/feed-icon-14x14.png){kind=icon}
Tools
Tools
| Item Type: | Article |
|---|---|
| Title: | Noncanonical effector functions of the T-memory-like T-PLL cell are shaped by cooperative TCL1A and TCR signaling |
| Creators: |
Oberbeck, S.  ORCID: https://orcid.org/0000-0002-0657-5281, Schrader, A., Warner, K., Jungherz, D., Crispatzu, G., von Jan, J., Chmielewski, M., Ianevski, A., Diebner, H.H. ORCID: https://orcid.org/0000-0002-7138-6372, Mayer, P., Kondo Ados, A., Wahnschaffe, L., Braun, T., Müller, T.A., Wagle, P., Bouska, A., Neumann, T., Pützer, S., Varghese, L., Pflug, N., Thelen, M. ORCID: https://orcid.org/0000-0002-2785-9726, Makalowski, J., Riet, N., Göx, H.J.M, Rappl, G., Altmüller, J. ORCID: https://orcid.org/0000-0003-4372-1521, Kotrová, M., Persigehl, T., Hopfinger, G., Hansmann, M.L., Schlößer, H. ORCID: https://orcid.org/0000-0002-1304-7719, Stilgenbauer, S., Dürig, J., Mougiakakos, D., von Bergwelt-Baildon, M., Roeder, I. ORCID: https://orcid.org/0000-0002-6741-0608, Hartmann, S., Hallek, M., Moriggl, R. ORCID: https://orcid.org/0000-0003-0918-9463, Brüggemann, M. ORCID: https://orcid.org/0000-0001-5514-5010, Aittokallio, T. ORCID: https://orcid.org/0000-0002-0886-9769, Iqbal, J., Newrzela, S., Abken, H. ORCID: https://orcid.org/0000-0002-4302-3240 and Herling, M.
|
| 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 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 Lck(pr)-hTCL1A(tg) 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. |
| Keywords: | Immunologic Memory, Knockout Mice, Proto-Oncogene Proteins, Signal Transduction, T-Cell Antigen Receptors, T-Cell Prolymphocytic Leukemia, T-Lymphocytes, Animals, Mice |
| Source: | Blood |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Volume: | 136 |
| Number: | 24 |
| Page Range: | 2786-2802 |
| Date: | 10 December 2020 |
| Additional Information: | Copyright © 2020 by The American Society of Hematology |
| Official Publication: | https://doi.org/10.1182/blood.2019003348 |
| External Fulltext: | View full text on PubMed Central |
| PubMed: | View item in PubMed |
Repository Staff Only: item control page
