Lymphoblastoid Cell Lines in Pharmacogenomics: How Applicable are They to Clinical Outcomes?

Stark, Amy L.; Dolan, M. Eileen

doi:10.2217/pgs.13.32

Cited by 8 publications

(6 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For instance, we have previously shown that lymphoblastoid cells preserve their inter-individual variation in adhesion to endothelial cells, an important leukocyte property in retinopathy [ 9 ]. Lymphoblastoid cell lines have been shown to be relevant not only to white blood cells but also to a diverse array of different tissues [ 8 , 10 – 12 ]. Recent findings of the GTEx study confirm the substantial overlap in the genetic architecture for gene expression between lymphoblastoid cells and other tissues [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Lymphoblastoid Cell Lines as a Tool to Study Inter-Individual Differences in the Response to Glucose

et al. 2016

View full text Add to dashboard Cite

BackgroundWhite blood cells have been shown in animal studies to play a central role in the pathogenesis of diabetic retinopathy. Lymphoblastoid cells are immortalized EBV-transformed primary B-cell leukocytes that have been extensively used as a model for conditions in which white blood cells play a primary role. The purpose of this study was to investigate whether lymphoblastoid cell lines, by retaining many of the key features of primary leukocytes, can be induced with glucose to demonstrate relevant biological responses to those found in diabetic retinopathy.MethodsLymphoblastoid cell lines were obtained from twenty-three human subjects. Differences between high and standard glucose conditions were assessed for expression, endothelial adhesion, and reactive oxygen species.ResultsCollectively, stimulation of the lymphoblastoid cell lines with high glucose demonstrated corresponding changes on molecular, cellular and functional levels. Lymphoblastoid cell lines up-regulated expression of a panel of genes associated with the leukocyte-mediated inflammation found in diabetic retinopathy that include: a cytokine (IL-1B fold change = 2.11, p-value = 0.02), an enzyme (PKCB fold change = 2.30, p-value = 0.01), transcription factors (NFKB-p50 fold change = 2.05, p-value = 0.01), (NFKB-p65 fold change = 2.82, p-value = 0.003), and an adhesion molecule (CD18 fold change = 2.59, 0.02). Protein expression of CD18 was also increased (p-value = 2.14x10-5). The lymphoblastoid cell lines demonstrated increased adhesiveness to endothelial cells (p = 1.28x10-5). Reactive oxygen species were increased (p = 2.56x10-6). Significant inter-individual variation among the lymphoblastoid cell lines in these responses was evident (F = 18.70, p < 0.0001).ConclusionsExposure of lymphoblastoid cell lines derived from different human subjects to high glucose demonstrated differential and heterogeneous gene expression, adhesion, and cellular effects that recapitulated features found in the diabetic state. Lymphoblastoid cells may represent a useful tool to guide an individualized understanding of the development and potential treatment of diabetic complications like retinopathy.

show abstract

Section: Introductionmentioning

confidence: 99%

Lymphoblastoid Cell Lines as a Tool to Study Inter-Individual Differences in the Response to Glucose

et al. 2016

View full text Add to dashboard Cite

show abstract

“…Genome-wide association studies have identified loci for drug-related phenotypes in humans, mice and lympoblastoid cells. 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 However, the yield of genetic loci has been low. In addition, successes have generally been limited to the idiosyncratic side effects of drugs.…”

Section: Introductionmentioning

confidence: 99%

Genetic screening reveals a link between Wnt signaling and antitubulin drugs

Bloom

Faridmoayer

et al. 2015

Pharmacogenomics J

View full text Add to dashboard Cite

The antitubulin drugs, paclitaxel (PX) and colchicine (COL), inhibit cell growth and are therapeutically valuable. PX stabilizes microtubules, while COL promotes their depolymerization. But, the drug concentrations that alter tubulin polymerization are hundreds of times higher than their clinically useful levels. To map genetic targets for drug action at single-gene resolution, we used a human radiation hybrid panel. We identified loci that affected cell survival in the presence of five compounds of medical relevance. For PX and COL, the zinc and ring finger 3 (ZNRF3) gene dominated the genetic landscape at therapeutic concentrations. ZNRF3 encodes an R-spondin regulated receptor that inhibits Wingless/Int (Wnt) signaling. Overexpression of the ZNRF3 gene shielded cells from antitubulin drug action, while small interfering RNA knockdowns resulted in sensitization. Further a potent pharmacological inhibitor of Wnt signaling, Wnt-C59, protected cells from PX and COL. Our results suggest that the antitubulin drugs perturb microtubule dynamics, thereby influencing Wnt signaling.

show abstract

“…This approach can uncover previously unrecognized mechanisms of drug response and provides information on the associated biological pathways. Lymphoblastoid cell lines (LCLs) constitute a well-established pharmacogenomic model for genome-wide expression profiling [ 18 , 19 ]. Although there has been some debate about biological noise related to confounding factors, LCLs have been used to assess gene sets involved in responses to anticancer drugs such as bleomycin, gemcitabine, cytosine arabinoside, and 5-fluorouracil [ 20 - 24 ].…”

Section: Introductionmentioning

confidence: 99%

Molecular insight into thiopurine resistance: transcriptomic signature in lymphoblastoid cell lines

Chouchana¹,

Fernández-Ramos²,

Dumont³

et al. 2015

Genome Med

View full text Add to dashboard Cite

BackgroundThere has been considerable progress in the management of acute lymphoblastic leukemia (ALL) but further improvement is needed to increase long-term survival. The thiopurine agent 6-mercaptopurine (6-MP) used for ALL maintenance therapy has a key influence on clinical outcomes and relapse prevention. Genetic inheritance in thiopurine metabolism plays a major role in interindividual clinical response variability to thiopurines; however, most cases of thiopurine resistance remain unexplained.MethodsWe used lymphoblastoid cell lines (LCLs) from healthy donors, selected for their extreme thiopurine susceptibility. Thiopurine metabolism was characterized by the determination of TPMT and HPRT activity. We performed genome-wide expression profiling in resistant and sensitive cell lines with the goal of elucidating the mechanisms of thiopurine resistance.ResultsWe determined a higher TPMT activity (+44%; P = 0.024) in resistant compared to sensitive cell lines, although there was no difference in HPRT activity. We identified a 32-gene transcriptomic signature that predicts thiopurine resistance. This signature includes the GTPBP4 gene coding for a GTP-binding protein that interacts with p53. A comprehensive pathway analysis of the genes differentially expressed between resistant and sensitive cell lines indicated a role for cell cycle and DNA mismatch repair system in thiopurine resistance. It also revealed overexpression of the ATM/p53/p21 pathway, which is activated in response to DNA damage and induces cell cycle arrest in thiopurine resistant LCLs. Furthermore, overexpression of the p53 target gene TNFRSF10D or the negative cell cycle regulator CCNG2 induces cell cycle arrest and may also contribute to thiopurine resistance. ARHGDIA under-expression in resistant cell lines may constitute a novel molecular mechanism contributing to thiopurine resistance based on Rac1 inhibition induced apoptosis and in relation with thiopurine pharmacodynamics.ConclusionOur study provides new insights into the molecular mechanisms underlying thiopurine resistance and suggests a potential research focus for developing tailored medicine.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-015-0150-6) contains supplementary material, which is available to authorized users.

show abstract

Lymphoblastoid Cell Lines in Pharmacogenomics: How Applicable are They to Clinical Outcomes?

Cited by 8 publications

References 22 publications

Lymphoblastoid Cell Lines as a Tool to Study Inter-Individual Differences in the Response to Glucose

Lymphoblastoid Cell Lines as a Tool to Study Inter-Individual Differences in the Response to Glucose

Genetic screening reveals a link between Wnt signaling and antitubulin drugs

Molecular insight into thiopurine resistance: transcriptomic signature in lymphoblastoid cell lines

Contact Info

Product

Resources

About