Next generation sequencing of mRNA of T-PLL patients and normal T-cell fractions

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 genotypic subgroups that may explain the heterogeneity of the disease. We found that T-PLL does not show a clear skewing in T cell receptor alpha (TRA), TRB gene usage and CDR3 stereotypy. In addition, multi-dimensional immuno-phenotyping and gene expression profiling did not reveal clear T-PLL subgroups. However, based on miRNA expression profiles, T-PLL samples did clearly cluster in subgroups. 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 expression was significantly correlated with increased white blood cell counts and poor survival. Furthermore, we found that overexpression of miR-200c/141 in T-PLL correlated with downregulation of their targets ZEB2 and TGFßR3, indicating that the TGFß pathway is affected. Our results thus highlight the emerging role for aberrantly expressed oncogenic miRNAs in T-PLL, thereby paving the way for new therapeutic targets in this disease. Overall design: mRNA seq of T-PLL patients compared to normal T cell fractions