Dysregulated signaling, proliferation and apoptosis impact on the pathogenesis of TCRγδ+ T cell large granular lymphocyte leukemia

• Published in: PloS one 2017, Vol.12 (4), p.e0175670-e0175670
• Main Authors: Kallemeijn, Martine J, de Ridder, Dick, Schilperoord-Vermeulen, Joyce, van der Klift, Michèle Y, Sandberg, Yorick, van Dongen, Jacques J M, Langerak, Anton W
• Format: Article
• Language: English
• Subjects: Adult; Age; Aged; Amino acids; Antigens; Apoptosis; Apoptosis Regulatory Proteins - genetics; Autoimmune diseases; Autophagy; Bacteria; Bioinformatica; Bioinformatics; Biology and Life Sciences; Blood; Blood & organ donations; Bone marrow; c-FLIP protein; Cancer; Caspase; Caspase-1; Cell growth; Cell morphology; Cell Proliferation; Computer programs; Cytotoxicity; Data bases; Disease; EPS; Etiology; Female; Gene expression; Gene Expression Profiling - methods; Gene Expression Regulation, Leukemic; Hematology; Humans; Immunology; Interleukin 1; Laboratories; Leukemia; Leukemia, Large Granular Lymphocytic - genetics; Leukemia, Large Granular Lymphocytic - pathology; Lymphatic leukemia; Lymphocytes; Lymphocytes T; Lymphoma; Male; Medicine and Health Sciences; Metabolism; Middle Aged; Morphology; Mutation; Neutropenia; Older people; Oligonucleotide Array Sequence Analysis - methods; Pathogenesis; Patients; Receptors, Antigen, T-Cell, gamma-delta - genetics; Research and Analysis Methods; Rheumatoid arthritis; Signal Transduction; T cell receptors; T-cell receptor; Tumor cells; Tumors; Zinc
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0175670

TCRγδ+ T-LGL leukemia is a rare form of chronic mature T cell disorders in elderly, which is generally characterized by a persistently enlarged CD3+CD57+TCRγδ+ large granular lymphocyte population in the peripheral blood with a monoclonal phenotype. Clinically, the disease is heterogeneous, most patients being largely asymptomatic, although neutropenia, fatigue and B symptoms and underlying diseases such as autoimmune diseases or malignancies are also often observed. The etiology of TCRγδ+ T-LGL proliferations is largely unknown. Here, we aimed to investigate underlying molecular mechanisms of these rare proliferations by performing gene expression profiling of TCRγδ+ T-LGL versus normal TCRγδ+ T cell subsets. From our initial microarray dataset we observed that TCRγδ+ T-LGL leukemia forms a separate group when compared with different healthy control TCRγδ+ T cell subsets, correlating best with the healthy TemRA subset. The lowest correlation was seen with the naive subset. Based on specific comparison between healthy control cells and TCRγδ+ T-LGL leukemia cells we observed up-regulation of survival, proliferation and hematopoietic system related genes, with a remarkable down-regulation of apoptotic pathway genes. RQ-PCR validation of important genes representative for the dataset, including apoptosis (XIAP, CASP1, BCLAF1 and CFLAR), proliferation/development (ID3) and inflammation (CD28, CCR7, CX3CR1 and IFNG) processes largely confirmed the dysregulation in proliferation and apoptosis. Based on these expression data we conclude that TCRγδ+ T-LGL leukemia is likely the result of an underlying aberrant molecular mechanisms leading to increased proliferation and reduced apoptosis.