The miR-200c/141-ZEB2-TGFβ axis is aberrant in human T-cell prolymphocytic leukemia

T-cell prolymphocytic leukemia (T-PLL) is mostly characterized by aberrant expansion of small- to medium-sized prolymphocytes with a mature post-thymic phenotype, high aggressiveness of the disease and poor prognosis. However, T-PLL is more heterogeneous with a wide range of clinical, morphological,...

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Veröffentlicht in:Haematologica (Roma) 2022-01, Vol.107 (1), p.143-153
Hauptverfasser: Erkeland, Stefan J, Stavast, Christiaan J, Schilperoord-Vermeulen, Joyce, Dal Collo, Giada, Van de Werken, Harmen J G, Leon, Leticia G, Van Hoven-Beijen, Antoinette, Van Zuijen, Iris, Mueller, Yvonne M, Bindels, Eric M, De Ridder, Dick, Kappers-Klunne, Mies C, Van Lom, Kirsten, Van der Velden, Vincent H J, Langerak, Anton W
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Sprache:eng
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Zusammenfassung:T-cell prolymphocytic leukemia (T-PLL) is mostly characterized by aberrant expansion of small- to medium-sized prolymphocytes with a mature post-thymic phenotype, high aggressiveness of the disease and poor prognosis. However, T-PLL is more heterogeneous with a wide range of clinical, morphological, and molecular features, which occasionally impedes the diagnosis. We hypothesized that T-PLL consists of phenotypic and/or genotypic subgroups that may explain the heterogeneity of the disease. Multi-dimensional immuno-phenotyping and gene expression profiling did not reveal clear T-PLL subgroups, and no clear T-cell receptor a or β CDR3 skewing was observed between different T-PLL cases. We revealed that the expression of microRNA (miRNA) is aberrant and often heterogeneous in T-PLL. We identified 35 miRNA that were aberrantly expressed in T-PLL with miR-200c/141 as the most differentially expressed cluster. High miR- 200c/141 and miR-181a/181b expression was significantly correlated with increased white blood cell counts and poor survival. Furthermore, we found that overexpression of miR-200c/141 correlated with downregulation of their targets ZEB2 and TGFβR3 and aberrant TGFβ1- induced phosphorylated SMAD2 (p-SMAD2) and p-SMAD3, indicating that the TGFβ pathway is affected in T-PLL. Our results thus highlight the potential role for aberrantly expressed oncogenic miRNA in T-PLL and pave the way for new therapeutic targets in this disease.
ISSN:0390-6078
1592-8721
DOI:10.3324/haematol.2020.263756