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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. and Glass, M. and Wahnschaffe, L. and Otte, M. and Mayer, P. and Franitza, M. and Altmüller, J. and Hallek, M. and Hüttelmaier, S. and 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
Publisher:Ferrata Storti Foundation
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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