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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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