Molecular insight into thiopurine resistance: transcriptomic signature in lymphoblastoid cell linesReport as inadecuate




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Genome Medicine

, 7:37

First Online: 18 April 2015Received: 18 November 2014Accepted: 03 March 2015

Abstract

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.

Abbreviations6-MP6-mercaptopurine

6-TG6-thioguanine

6-TGTP6-thioguanosine triphosphate

ALLAcute lymphoblastic leukemia

AMPAdenosine monophosphate

ATPAdenosine triphosphate

cDNAComplementary DNA

DAVIDDatabase for annotation visualization and integrated discovery

EBVEpstein-Barr virus

gDNAgenomic DNA

GEOGene expression omnibus

GOGene ontology

HPRTHypoxanthine-guanine phosphoribosyltransferase

IMPInosine monophosphate

LCLLymphoblastoid cell lines

mtDNAmitochondrial DNA

NCBINational center for biotechnology information

NLGIPNational laboratory for the genetics of Israeli populations

PAMPrediction analysis of microarrays

PCAPrincipal component analysis

RMARobust multi-array average

RT-qPCRReverse transcriptase-quantitative polymerase chain reaction

TPMTThiopurine S-methyltransferase

Electronic supplementary materialThe online version of this article doi:10.1186-s13073-015-0150-6 contains supplementary material, which is available to authorized users.

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Author: Laurent Chouchana - Ana Aurora Fernández-Ramos - Florent Dumont - Catherine Marchetti - Irène Ceballos-Picot - Philippe B

Source: https://link.springer.com/







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