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 pro-lymphocytes 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, whereas no clear T cell receptor alpha (TRA) or beta (TRB) CDR3 skewing was observed between different T-PLL cases. We revealed that the expression of miRNAs is aberrant and often heterogeneous in T-PLL. We identified 35 miRNAs 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 TGF-β1-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 miRNAs in T-PLL and pave the way for new diagnostic targets in this disease.

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Authors: Stefan J Erkeland, Christiaan J Stavast, Joyce Schilperoord-Vermeulen, Giada Dal Collo, Harmen J G Van de Werken, Leticia G Leon, Antoinette Van Hoven-Beijen, Iris Van Zuijen, Yvonne M Mueller, Eric M Bindels, Dick De Ridder, Mies C Kappers-Klunne, Kirsten Van Lom, Vincent H J Van der Velden, Anton W Langerak