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Noncanonical function of AGO2 augments T-cell receptor signaling in T-cell prolymphocytic leukemia

Item Type:Article
Title:Noncanonical function of AGO2 augments T-cell receptor signaling in T-cell prolymphocytic leukemia
Creators Name:Braun, T. and Stachelscheid, J. and Bley, N. and Oberbeck, S. and Otte, M. and Müller, T.A. and Wahnschaffe, L. and Glaß, M. and Ommer, K. and Franitza, M. and Gathof, B. and Altmüller, J. and Hallek, M. and Auguin, D. and Hüttelmaier, S. and Schrader, A. and Herling, M.
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 AGO2 gene than the adjacent MYC locus as the affected minimally amplified genomic region. AGO2 has been understood as a pro-tumorigenic key regulator of microRNA (miR) processing. 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. Moreover, AGO2 elicited immediate, rather than 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 phospho-activation. 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 post-transcriptional modi-fications by LCK. This novel TCR-associated non-canonical 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.
Keywords:T-PLL, AGO2, T-Cell Receptor, miR expression, ZAP70
Source:Cancer Research
Publisher:American Association for Cancer Research
Page Range:1818-1831
Date:1 May 2022
Official Publication:https://doi.org/10.1158/0008-5472.CAN-21-1908
PubMed:View item in PubMed

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