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Micro-RNA networks in T-cell prolymphocytic leukemia reflect T-cell activation and shape DNA damage response and survival pathways

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Item Type:Article
Title:Micro-RNA networks in T-cell prolymphocytic leukemia reflect T-cell activation and shape DNA damage response and survival pathways
Creators Name:Braun, T., Glass, M., Wahnschaffe, L., Otte, M., Mayer, P., Franitza, M., Altmüller, J., Hallek, M., Hüttelmaier, S., Schrader, A. and Herling, M.
Abstract:T-cell prolymphocytic leukemia (T-PLL) is a poor-prognostic mature T-cell malignancy. It typically presents with exponentially rising lymphocyte counts, splenomegaly, and bone marrow infiltration. Effective treatment options are scarce and a better understanding of T-PLL's pathogenesis is desirable. Activation of the TCL1 proto-oncogene and loss-of-function perturbations of the tumor suppressor ATM are T-PLL's genomic hallmarks. The leukemic cell reveals a phenotype of active T-cell receptor (TCR) signaling and aberrant DNA-damage responses. Regulatory networks based on the profile of micro-RNAs (miRs) have not been described for T-PLL. In a combined approach of small-RNA and transcriptome sequencing in 46 clinically and moleculary well-characterized T-PLL, we identified a global T-PLL-specific miR expression profile that involves 34 significantly deregulated miR species. This pattern strikingly resembled miR-ome signatures of TCR-activated T-cells. By integrating these T-PLL miR profiles with transcriptome data, we uncovered regulatory networks associated with cell survival signaling and DNA-damage response pathways. Despite a miR-ome that discerned leukemic from normal T-cells, there were also robust subsets of T-PLL defined by a small set of specific miRs. Most prominently, miR-141 and the miR-200c-cluster separated cases into two major subgroups. Furthermore, increased expression of miR-223-3p as well as reduced expression of miR-21 and the miR-29 cluster were associated with more activated T-cell phenotypes and more aggressive disease presentations. Based on the implicated pathobiological role of these miR deregulations, targeting strategies around their effectors appear worth pursuing. We also established a combinatorial miR-based overall survival score for T-PLL (miROS-T-PLL), that might improve current clinical stratifications.
Keywords:DNA Damage, T-Cell Prolymphocytic Leukemia, Lymphocyte Activation, MicroRNAs, T-Lymphocytes
Source:Haematologica
ISSN:0390-6078
Publisher:Ferrata Storti Foundation
Volume:107
Number:1
Page Range:187-200
Date:January 2022
Official Publication:https://doi.org/10.3324/haematol.2020.267500
PubMed:View item in PubMed

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