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Noncanonical Function of AGO2 Augments T-cell Receptor Signaling in T-cell Prolymphocytic Leukemia
Open accessPublished version of a preprint
Abstract
T-cell prolymphocytic leukemia (T-PLL) is a chemotherapy-refractory T-cell malignancy with limited therapeutic options and a poor prognosis. Current disease concepts implicate TCL1A oncogene-mediated enhanced T-cell receptor (TCR) signaling and aberrant DNA repair as central perturbed pathways. We discovered that recurrent gains on chromosome 8q more frequently involve the argonaute RISC catalytic component 2 (AGO2) gene than the adjacent MYC locus as the affected minimally amplified genomic region. AGO2 has been understood as a protumorigenic key regulator of miRNA (miR) processing. Here, in primary tumor material and cell line models, AGO2 overrepresentation associated (i) with higher disease burden, (ii) with enhanced in vitro viability and growth of leukemic T cells, and (iii) with miR-omes and transcriptomes that highlight altered survival signaling, abrogated cell-cycle control, and defective DNA damage responses. However, AGO2 elicited also immediate, rather non–RNA-mediated, effects in leukemic T cells. Systems of genetically modulated AGO2 revealed that it enhances TCR signaling, particularly at the level of ZAP70, PLCγ1, and LAT kinase phosphoactivation. In global mass spectrometric analyses, AGO2 interacted with a unique set of partners in a TCR-stimulated context, including the TCR kinases LCK and ZAP70, forming membranous protein complexes. Models of their three-dimensional structure also suggested that AGO2 undergoes posttranscriptional modifications by ZAP70. This novel TCR-associated noncanonical function of AGO2 represents, in addition to TCL1A-mediated TCR signal augmentation, another enhancer mechanism of this important deregulated growth pathway in T-PLL. These findings further emphasize TCR signaling intermediates as candidates for therapeutic targeting. Significance: The identification of AGO2-mediated activation of oncogenic T cells through signal amplifying protein–protein interactions advances the understanding of leukemogenic AGO2 functions and underlines the role of aberrant TCR signaling in T-PLL.
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Metadata
- Authors
- Braun, T., Stachelscheid, J., Bley, N., Oberbeck, S., Otte, M., Müller, T. A., Wahnschaffe, L., Glaß, M., Ommer, K., Franitza, M., Gathof, B., Altmüller, J., Hallek, M., Auguin, D., Hüttelmaier, S., Schrader, A., & Herling, M.
- Affiliations
- University of Cologne (DE)
- Martin Luther University Halle-Wittenberg (DE)
- Université d'Orléans (FR)
- Corresponding author
- Herling, Marco
- ORCID
- Venue
- Cancer Research
- Published
- 2022-03-08
- Volume
- 82
- Issue
- 9
- Pages
- 1818-1831
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W4220910262
- Cited by
- 14
- References
- 1
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 3 · 2023: 6 · 2022: 2
- FWCI
- 1.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Funders
- DFG Research Unit FOR1961 (HE3553/4-2)
- Köln Fortune program
- Fritz Thyssen Foundation (10.15.2.034MN)
- EU Transcan-2 consortium “ERANET-PLL”
- ERAPerMed consortium “JAKSTAT-TARGET
- German José Carreras Leukemia Foundation (DJCLS 03 F/2016)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and Retrovirus Studies
- Health Sciences › Medicine › Hematology › Chronic Lymphocytic Leukemia Research
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Keywords
- Argonaute 2, T-cell prolymphocytic leukemia, T cell receptor signaling, chromosome 8q gain, TCL1, ZAP-70, Lck, PLCγ1, protein-protein interaction, post-translational modification, DNA damage response, cell cycle regulation, microRNA processing, protein complex structure
- MeSH terms
- Humans, Phosphorylation, Receptors, Antigen, T-Cell, T-Lymphocytes, Signal Transduction, Leukemia, Prolymphocytic, T-Cell, MicroRNAs
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