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Genomic and functional studies in T-Acute Lymphoblastic Leukemia patients exhibiting clonal T Cell Receptor γ and δ gene rearrangement

ABSTRACT: T-cell Acute Lymphoblastic Leukemia (T-ALL) is a lymphoid malignancy characterized by clonal proliferation of immature thymocytes arrested at particular stage of differentiation. Earlier studies from our lab have demonstrated that 30% of Indian T-ALL patients exhibited clonal rearrangement of both TCR γ and δ genes. The survival was higher in T-ALL patients showing clonal rearrangements for TCR γ and δ genes. In the present study, we aimed at investigating the gene expression profiles of TCR γδ+ T-ALL patients and correlating it with functional analysis to understand the reasons for increased survival in these patients. Our studies demonstrate differential expression of genes in TCR γδ clonal T-ALL compared to non TCR γδ clonal T-ALL patients. Functional annotation of significantly upregulated genes (p<0.05) in TCR γδ+ T-ALL patients showed involvement in antigen processing and presentation, cell-cell communication, apoptosis, cell adhesion molecules and immune synapse pathways. Expression of eight selected genes (SMAD3, NFkB1, HLA-DQB1, SOCS2, CISH, FASLG, RXRA,and IFNβ1) was validated in TCRαβ+ and TCRγδ+ subgroups of T-ALL patients using quantitative Real-time PCR. Studies focusing on functional aspects of the gene(s) identified from gene expression profile would aid in developing future therapeutic strategies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE37389 | GEO | 2016/04/25

SECONDARY ACCESSION(S): PRJNA159717

REPOSITORIES: GEO

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Project description:γδ T cells are lymphocytes that function in both innate and adaptive immune responses, and our laboratory has previously reported that both bovine and human γδ T cells are primed for secondary responses by tannin components of the unripe apple peel (APP). In this report we began to investigate the mechanism by which priming occurs. We performed a microarray analysis on sorted bovine γδ T cells treated with APP and observed significant increases in transcripts encoding select inflammatory cytokines, such as GM-CSF, IL-8, and IL-17, but not markers of TCR stimulation such as IFNγ. When injected into the gut of mice, APP induced a robust influx of neutrophils into both the blood and peritoneum as measured by FACS. Importantly, both GM-CSF and IL-8 proteins were detected in these animals. Further studies were performed using the human γδ T cell-line MOLT-14, as large numbers of cells were required for subsequent experiments. Using these cells we found that both the GM-CSF and IL-8 mRNAs were significantly upregulated and stabilized in cells treated with APP. Finally, we show that the ERK1/2 MAPK pathway was activated in APP-treated MOLT-14 cells, and that this pathway plays a role in the mRNA stabilization we observed. Together, our data describe a unique inflammatory response in bovine, murine, and human γδ T cells in response to APP, and suggest that mRNA stability mechanisms could account for the priming phenotype we previously observed.APP has a distinctive gamma delta T cells specific priming activity. Keywords: comparison of 2 treatment types, tannin, gamma delta T cells To begin to understand the effects of APP in innate immunity, we investigated the global gene expression profiles of stimulated bovine gamma delta T cells. Peripheral blood from 2 neonatal bovine calves was collected. gamma delta T cells were sorted to >97% purity using a FACS Vantage. Cells were placed in culture and stimulated with either an aqueous extract of APP (42.2ug/ml) or PBS for 4 hours after which RNA was extracted and processed for microarray analysis following standard protocols from Affymetrix.

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Genomic and functional studies in T-Acute Lymphoblastic Leukemia patients exhibiting clonal T Cell Receptor γ and δ gene rearrangement

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