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Non Hodgkin-Lymphoma
Micro-RNA networks in T-cell prolymphocytic leukemia reflect T-cell activation and shape DNA damage response and survival pathways
Till Braun,1* Markus Glaß,2* Linus Wahnschaffe,1* Moritz Otte,1 Petra Mayer,1 Marek Franitza,3 Janine Altmüller,3 Michael Hallek,1 Stefan Hüttelmaier,2# Alexandra Schrader,1# and Marco Herling1#
1Department I of Internal Medicine, Center for Integrated Oncology (CIO), Aachen-Bonn- Cologne-Duesseldorf, Excellence Cluster for Cellular Stress Response and Aging- Associated Diseases (CECAD), Center for Molecular Medicine Cologne (CMMC), University of Cologne (UoC), Cologne; 2Institute of Molecular Medicine, Section for Molecular Cell Biology, Faculty of Medicine, Martin Luther University Halle-Wittenberg, Charles Tanford Protein Center, Halle, and 3Cologne Center for Genomics, Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany
*TB, MG and LW contributed equally as co-first authors. #SH, AS and MH contributed equally as co-senior authors.
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 microRNA (miR) have not been described for T-PLL. In a combined approach of small-RNA and transcriptome sequencing in 46 clinically and moleculary well-character- ized T-PLL, we identified a global T-PLL-specific miR expression profile that involves 34 significantly deregulated miR species. This pattern strik- ingly resembled miR-ome signatures of TCR-activated T cells. By inte- grating 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 miR. 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 estab- lished a combinatorial miR-based overall survival score for T-PLL (miROS-T-PLL), that might improve current clinical stratifications.
Introduction
T-cell prolymphocytic leukemia (T-PLL) is a neoplasm of post-thymic T cells.1 It represents the most frequent mature T-cell leukemia in Western countries, however, with an incidence of 2 per million per year, it is still classified as an orphan disease.2 T-PLL patients typically present at a median age of about 65 years, with exponentially rising lymphocytosis, marked bone marrow infiltra- tion, and splenomegaly.3 Phenotypically, T-PLL cells resemble mature, antigen- experienced T cells.4,5 The aggressive growth of T-PLL cells is paralleled by a refractory behavior towards most conventional chemotherapies.6 The current
Ferrata Storti Foundation
Haematologica 2022 Volume 107(1):187-200
Correspondence:
MARCO HERLING
Marco.Herling@medizin.uni-leipzig.de
Received: July 20, 2020.
Accepted: November 6, 2020. Pre-published: November 19, 2020.
https://doi.org/10.3324/haematol.2020.267500 ©2022 Ferrata Storti Foundation
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