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- Title
Dysregulated signaling, proliferation and apoptosis impact on the pathogenesis of TCRγδ+ T cell large granular lymphocyte leukemia.
- 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.
- Abstract
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.
- Subjects
APOPTOSIS; LEUKEMIA diagnosis; HEMATOLOGIC malignancies; GENOTYPE-environment interaction; GENETIC pleiotropy; GENETICS; DISEASE risk factors; THERAPEUTICS
- Publication
PLoS ONE, 2017, Vol 12, Issue 4, p1
- ISSN
1932-6203
- Publication type
Article
- DOI
10.1371/journal.pone.0175670