Lihui Wang

University of Liverpool, Liverpool, England, United Kingdom

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Publications (21)138.62 Total impact

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    ABSTRACT: Approximately 40% of chronic myeloid leukaemia (CML) patients receiving imatinib fail treatment. There is an increased risk of CML in subjects with Glutathione S-transferase (GST) GSTT1 and GSTM1 gene deletions, and the GSTP1 single nucleotide polymorphism (SNP) Ile105Val (GSTP1*B; rs1695); however their effect on imatinib treatment outcome is not known. Here we assess the role of these GSTs in relation to imatinib treatment outcome in 193 CML patients. GSTT1 deletion alone, or in combination with the GSTM1 gene deletion, significantly increased the likelihood of imatinib failure (P = 0.021 and P < 0.001 respectively). The GSTP1*B SNP was not associated with time to imatinib failure. GSTT1 and GSTM1 gene loss are therefore important determinants of imatinib failure in CML. Screening for GSTT1 and GSTM1 gene deletions at diagnosis may identify patients who may be better treated by an alternative therapy.Clinical Pharmacology & Therapeutics (2014); Accepted article preview online 04 September 2014; doi:10.1038/clpt.2014.176.
    Clinical Pharmacology &#38 Therapeutics 09/2014; · 6.85 Impact Factor
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    ABSTRACT: The expression and activity of the uptake transporter human organic cation transporter 1 (hOCT1; SLC22A1) is an independent predictor of response to imatinib treatment in chronic myeloid leukaemia (CML) patients. We have recently shown that peroxisome proliferator-activated receptors (PPAR) activation can increase the killing effect of imatinib in CML cells, due to upregulated hOCT1 gene expression and increased imatinib uptake. To investigate the role of activation of nuclear receptors other than PPAR in the transcriptional regulation of hOCT1, CML cells were treated with agonists for 13 adopted orphan receptors and endocrine receptors. It was found that hOCT1 expression was upregulated by the agonists for pregnane X receptor (PXR), retinoid acid receptor (RAR) and retinoid X receptor (RXR) in CML cell line and primary CML cells (p=0.04; Wilcoxon rank test). Hence, agonists for PXR, RAR and RXR may be potentially used to improve the efficacy of imatinib in CML patients.This article is protected by copyright. All rights reserved.
    European Journal Of Haematology 07/2014; · 2.55 Impact Factor
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    ABSTRACT: BACKGROUND: Population based data suggest the proportion of patients failing imatinib in chronic myeloid leukaemia (CML) is higher than the reported one-third of patients in clinical trials. Clinical trials have demonstrated second generation tyrosine kinase inhibitors (TKI) dasatinib and nilotinib can restore complete cytogenetic remission (CCR) and major molecular response (MMR) to many patients failing imatinib, but their impact in the general population is not clear. DESIGN AND METHODS: We report CML outcome in a population of 2.3 million people in a geographically contiguous area of North West England and North Wales. RESULTS: Between 2003 and 2009, 192 new CML cases were diagnosed, of whom 184 were in chronic phase and 160 started on imatinib. The maximal CCR rate was 65% at 24 months and the maximal MMR rate was 50% at 36 months. Patients diagnosed since second generation TKI became available for imatinib failure had a more rapid cumulative CCR and MMR rate and a significantly improved progression free survival (p=0.022) than those diagnosed before this time. CONCLUSION: The study indicates that second generation TKI have improved CML outcome in the general population.
    Leukemia research 04/2013; · 2.36 Impact Factor
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    ABSTRACT: Several groups have shown that that the BCR-ABL1 transcript level measured at 3 or 6 months after starting treatment with tyrosine kinase inhibitors strongly predicts for clinical outcomes for CML patients. In this work we asked whether the prognostic value of the 3-month transcript level could be improved by combining the 3- and 6- month results. We classified patients treated with imatinib and patients treated with dasatinib according to their transcript levels at 3 months and 6 months. The patients who met the 3-month landmark but failed the 6-month one had outcomes identical to those of patients who met both landmarks whereas the patients who failed the first landmark but met the second one had prognoses similar to those who failed both landmarks. In summary early intervention strategies can be based robustly just on the transcript level at 3 months. (ClinicalTrials.gov Identifier: NCT01460693).
    Blood 02/2013; · 9.78 Impact Factor
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    ABSTRACT: Although the prognosis of chronic myeloid leukaemia (CML) patients treated with imatinib is good, many fail to develop an optimal response or lose one. This heterogeneity could be attributed to the presence of human organic cation transporter-1 (hOCT1) single nucleotide polymorphisms (SNPs). Here, we analyse the effect of 23 hOCT1 SNPs on imatinib treatment outcome in newly-diagnosed CML patients, using MassARRAY sequencing and pyrosequencing. The only SNP associated with outcome was M420del (rs35191146) with patients with the M420del demonstrating an increased probability of imatinib treatment failure. In CML cell lines transfected with M420del and/or M408V, M420del significantly decreased imatinib uptake, but this effect was countered if the M408V (rs628031) SNP was also present. A similar effect was seen for the uptake of the hOCT1 substrates TEA(+) and ASP(+). Finally, apparent hOCT1 mRNA levels were studied using both our earlier primers covering the M420del and another set that did not. Different mRNA expression was observed, explaining the disparity in published data on the prognostic importance of hOCT1 mRNA and highlighting the importance of avoiding common SNP sites in primer design. These data demonstrate that the common M420del SNP can modulate the outcome of imatinib treatment.
    Blood 12/2012; · 9.78 Impact Factor
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    ABSTRACT: Low pretreatment expression of the imatinib uptake transporter human organic cation transporter 1 (hOCT1) is associated with inferior complete cytogenetic response rates, progression-free survival, and overall survival in imatinib-treated chronic myeloid leukemia (CML). Upregulation of hOCT1 can therefore increase the uptake of imatinib. The hOCT1 gene is transactivated by hepatocyte nuclear factor 4α in human liver, and peroxisome proliferator-activated receptors (PPAR) α and γ activation increases OCT1 expression in mouse hepatocytes. Here we report that no isoform of hepatocyte nuclear factor 4α is expressed in CML lines or in CML primary cells. In contrast, both PPARα and γ were expressed in all CML cell lines and primary cells studied. PPARα agonist treatment increased imatinib killing of CML KCL22 cells and primitive CD34(+) cells, and also upregulates hOCT1 gene expression and increases imatinib uptake into KCL22 cells and primary cells. PPARα agonists might potentially be of clinical use in CML patients failing imatinib.
    Experimental hematology 06/2012; 40(10):811-819.e2. · 3.11 Impact Factor
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    ABSTRACT: We studied BCR-ABL1 transcript levels in patients with chronic myeloid leukemia in chronic phase (CML-CP) at 3, 6, and 12 months after starting imatinib to identify molecular milestones that would predict for overall survival (OS) and other outcomes more reliably than serial marrow cytogenetics. We analyzed 282 patients with CML-CP who received imatinib 400 mg/d as first-line therapy followed by dasatinib or nilotinib if treatment with imatinib failed. We used a receiver operating characteristic curve to identify the cutoffs in transcript levels at 3, 6, and 12 months that would best predict patient outcome. We validated our findings in an independent cohort of 95 patients treated elsewhere. Patients with transcript levels of more than 9.84% (n = 68) at 3 months had significantly lower 8-year probabilities of OS (56.9% v 93.3%; P < .001), progression-free survival, cumulative incidence of complete cytogenetic response, and complete molecular response than those with higher transcript levels. Similarly, transcript levels of more than 1.67% (n = 87) at 6 months and more than 0.53% (n = 93) at 12 months identified high-risk patients. However, transcript levels at 3 months were the most strongly predictive for the various outcomes. When we compared OS for the groups defined molecularly at 6 and 12 months with the usual cytogenetic milestones, categorization by transcript numbers was the only independent predictor for OS (relative risk, 0.207; P < .001 and relative risk, 0.158; P < .001, respectively). A single measurement of BCR-ABL1 transcripts performed at 3 months is the best way to identify patients destined to fare poorly, thereby allowing early clinical intervention.
    Journal of Clinical Oncology 11/2011; 30(3):232-8. · 18.04 Impact Factor
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    ABSTRACT: Molecular testing for the BCR-ABL1 fusion gene by real time quantitative polymerase chain reaction (RT-qPCR) is the most sensitive routine approach for monitoring the response to therapy of patients with chronic myeloid leukaemia. In the context of tyrosine kinase inhibitor (TKI) therapy, the technique is most appropriate for patients who have achieved complete cytogenetic remission and can be used to define specific therapeutic milestones. To achieve this effectively, standardization of the laboratory procedures and the interpretation of results are essential. We present here consensus best practice guidelines for RT-qPCR testing, data interpretation and reporting that have been drawn up and agreed by a consortium of 21 testing laboratories in the United Kingdom and Ireland in accordance with the procedures of the UK Clinical Molecular Genetics Society.
    British Journal of Haematology 03/2011; 153(2):179-90. · 4.94 Impact Factor
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    ABSTRACT: We and others have reported that vaccination of chronic myeloid leukaemia (CML) patients with e14a2 BCR-ABL junctional peptides can elicit moderate but transient T cell responses. To determine whether CML patients may be tolerised to BCR-ABL, here we used the same schedule to vaccinate 5 healthy subjects. Although IFN-γ and granzyme-B production, and proliferative responses to the vaccine peptides were detected in all 5 cases, responses were statistically similar to CML patients. CML patients are therefore not appreciably tolerised to BCR-ABL, and junctional peptides may only be moderately immunogenic, underlining the importance of antigen immunogenicity when designing vaccination strategies.
    Leukemia research 03/2011; 35(3):369-72. · 2.36 Impact Factor
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    ABSTRACT: Activation of the EVI-1 oncogene has been reported in acute myeloid leukemia, chronic myeloid leukemia (CML) in blast crisis, and less commonly, in chronic-phase CML patients. We screened an unselected cohort of 75 chronic-phase CML patients who had failed imatinib for expression of EVI-1 and sought a correlation with subsequent outcome on the second-generation tyrosine kinase inhibitors dasatinib (n = 61) or nilotinib (n = 14). The 8 patients (10.7%) who expressed EVI-1 transcripts detectable by real-time polymerase chain reaction had significantly lower event-free survival, progression-free survival, and overall survival than patients with undetectable transcript. The predictive value of EVI-1 expression was validated in an independent cohort. In a multivariate analysis, EVI-1 expression status and the best cytogenetic response obtained on imatinib were the only independent predictors for overall survival, progression-free survival, and event-free survival. Our data suggest that screening for EVI-1 expression at the time of imatinib failure may predict for response to second-line TKI therapy and consequently aid clinical management.
    Blood 12/2010; 116(26):6014-7. · 9.78 Impact Factor
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    ABSTRACT: Clinical presentation of chronic myeloid leukemia (CML) requires not only the deregulated tyrosine kinase BCR-ABL, but also the failure of an immune response against BCR-ABL-expressing cells. T-cell responses against BCR-ABL and other antigens are well-described, but their relevance to the in vivo control of CML is unclear. The suppressive role of naturally occurring T regulatory (T-reg) cells in antitumor immunity is well-established, although little is known about their role in modulating the T-cell response to BCR-ABL. Naturally occurring T-reg cells were characterized and quantified by flow cytometry in 39 CML patients and 10 healthy donors. Their function was studied by observing their effect on responses to purified protein derivative, a recall antigen, and on the response of an autologous T-cell line recognizing BCR-ABL. T-reg cells were CD4(+), CD25(+), FOXP3(+), CD127(low), and CD62L(high). T-reg numbers in patients in complete cytogenetic remission were significantly lower than in patients not in complete cytogenetic remission (p < 0.01). T-reg cell depletion using anti-CD25 selection enhanced proliferative responses to purified protein derivative. Furthermore, the interferon-γ and/or granzyme-B production of effector cells specific for viral peptides or a BCR-ABL HLA-A3-restricted peptide was inhibited when autologous T-reg cells were present. Taken together, these data suggest a role for T-reg cells in limiting immune responses in CML patients and this may include immune responses to BCR-ABL. The increased frequency of T-reg cells in patients with high levels of BCR-ABL transcripts indicates that an immune mechanism may be important in the control of CML.
    Experimental hematology 12/2010; 38(12):1209-18. · 3.11 Impact Factor
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    ABSTRACT: Serial quantitation of BCR-ABL mRNA levels is an important indicator of therapeutic response for patients with chronic myelogenous leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia, but there is substantial variation in the real-time quantitative polymerase chain reaction methodologies used by different testing laboratories. To help improve the comparability of results between centers we sought to develop accredited reference reagents that are directly linked to the BCR-ABL international scale. After assessment of candidate cell lines, a reference material panel comprising 4 different dilution levels of freeze-dried preparations of K562 cells diluted in HL60 cells was prepared. After performance evaluation, the materials were assigned fixed percent BCR-ABL/control gene values according to the International Scale. A recommendation that the 4 materials be established as the first World Health Organization International Genetic Reference Panel for quantitation of BCR-ABL translocation by real-time quantitative polymerase chain reaction was approved by the Expert Committee on Biological Standardization of the World Health Organization in November 2009. We consider that the development of these reagents is a significant milestone in the standardization of this clinically important test, but because they are a limited resource we suggest that their availability is restricted to manufacturers of secondary reference materials.
    Blood 11/2010; 116(22):e111-7. · 9.78 Impact Factor
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    ABSTRACT: Genetic as well as epigenetic alterations are a hallmark of both epithelial and haematological malignancies. High throughput screens are required to identify epigenetic markers that can be useful for diagnostic and prognostic purposes across malignancies. Here we report for the first time the use of the MIRA assay (methylated CpG island recovery assay) in combination with genome-wide CpG island arrays to identify epigenetic molecular markers in childhood acute lymphoblastic leukemia (ALL) on a genome-wide scale. We identified 30 genes demonstrating methylation frequencies of > or =25% in childhood ALL, nine genes showed significantly different methylation frequencies in B vs T-ALL. For majority of the genes expression could be restored in methylated leukemia lines after treatment with 5-azaDC. Forty-four percent of the genes represent targets of the polycomb complex. In chronic myeloid leukemia (CML) two of the genes, (TFAP2A and EBF2), demonstrated increased methylation in blast crisis compared to chronic phase (P < 0.05). Furthermore hypermethylation of an autophagy related gene ATG16L2 was associated with poorer prognosis in terms of molecular response to Imatinib treatment. Lastly we demonstrated that ten of these genes were also frequently methylated in common epithelial cancers. In summary we have identified a large number of genes showing frequent methylation in childhood ALL, methylation status of two of these genes is associated with advanced disease in CML and methylation status of another gene is associated with prognosis. In addition a subset of these genes may act as epigenetic markers across hematological malignancies as well as common epithelial cancers.
    Molecular Cancer 02/2010; 9:44. · 5.13 Impact Factor
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    ABSTRACT: Chronic myeloid leukemia is characterized by a reciprocal translocation between chromosomes 9 and 22, creating the fusion gene BCR-ABL. The clinical significance of the type of BCR-ABL transcript in newly diagnosed patients in chronic phase treated with imatinib 400 mg from initial diagnosis remains unknown. We analyzed the clinical outcome of 78 newly diagnosed chronic phase patients, aged 16 or over, treated with imatinib 400 mg. Of these, 71 expressed either e13a2 or e14a2 transcripts. BCR-ABL transcripts were assayed by quantitative real-time polymerase chain reaction. After 12 months of treatment, 54% of the e14a2 patients had achieved a complete cytogenetic response, compared to 25% of the e13a2 patients (p=0.01). Kaplan-Meier analysis of the time to achieve complete cytogenetic response revealed that e14a2 patients had more rapid response rates, compared to e13a2 patients (p=0.006). e14a2 patients had a higher event-free survival rate in the first 12 months of treatment, although overall survival did not differ significantly between the patients with the two types of transcript. Human organic cation transporter protein 1 mRNA levels did not differ between the patients with the two types of transcript. The pre-treatment pCrKL/CrKL ratio (a surrogate marker of BCR-ABL tyrosine kinase activity) was higher in patients with e13a2 transcripts than in those with e14a2 (p=0.017). Patients expressing the e14a2 transcript type have a higher rate and more rapid complete cytogenetic responses than e13a2-expressing patients, which may be due to higher BCR-ABL tyrosine kinase activity. Knowledge of the transcript type may yield additional prognostic information, although this requires testing on larger datasets.
    Haematologica 09/2009; 94(10):1362-7. · 5.94 Impact Factor
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    ABSTRACT: The fusion oncoprotein bcr-abl that characterizes chronic myeloid leukemia (CML) is a leukemia-specific antigen, which may be immunogenic in vivo. KQSSKALQR and GFKQSSKAL, peptide sequences spanning the b3a2 bcr-abl junction, have affinity for HLA-A3 and HLA-B8, respectively, and we have shown the presence of KQSSKALQR on the surface of CML cells. We analyzed the existence of bcr-abl-specific T cells in vivo and correlated their presence to contemporary disease burden. We investigated circulating CD8+ T lymphocytes directed against the bcr-abl junction, using fluorochrome-labeled tetramers of HLA-A3 with KQSSKALQR and of HLA-B8 with GFKQSSKAL, and flow cytometry analysis. Using chromium-release assays and interferon-g ELISPOT assays, we also studied the functionality of these expanded T cells. Eight of 12 b3a2+ HLA-A3+ and/or HLA-B8+ CML patients studied serially on at least three occasions had bcr-abl junction-specific CD8+ T cells. Specific T cells were more likely to be found in patients with a low leukemic burden (p=0.03). Three of 18 HLA-A3+ and/or HLA-B8+ healthy donors had bcr-abl junction-specific T cells, though these were not detected in any of 13 subjects who were HLA-A3- and HLA-B8-. Bcr-abl-specific T cells were expandable in vitro in three of seven healthy donors and five of seven CML patients. Bcr-abl-specific T cells are detectable in CML patients, and might contribute to leukemic control. The occurrence of specific CD8+ T cells in some healthy donors might represent an immune response to occult BCR-ABL rearrangements.
    Haematologica 11/2005; 90(10):1315-23. · 5.94 Impact Factor
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    Blood 09/2005; 106(3):1133-4; author reply 1134. · 9.78 Impact Factor
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    ABSTRACT: Imatinib is a tyrosine kinase inhibitor that is effective in the treatment of chronic myeloid leukemia (CML). Not all patients achieve cytogenetic response. Some patients even lose the initial cytogenetic response. In this study, we investigated the active cellular transport of imatinib to gain a better understanding of the possible mechanisms of imatinib resistance. We used the leukemic cell line CCRFCEM and its drug-resistant subline VBL(100) to measure the uptake of carbon 14 ((14)C)-labeled imatinib. Imatinib uptake was temperature dependent, indicative of an active uptake process. Additionally, incubations with transport inhibitors showed that verapamil, amantadine, and procainamide, inhibitors of the human organic cation transporter 1 (hOCT1), significantly decreased imatinib uptake into CEM cells, whereas the inhibition of hOCT2 or hOCT3 had no effect, indicating that influx into the cells is an active process likely to be mediated by hOCT1. Studies using transfected MDCK cell lines revealed an active efflux component attributable to MDR1 (ABCB1). Both hOCT1 and MDR1 were expressed in CML primary cells and cell lines. The results indicate that active transport processes mediate the influx and efflux of imatinib. Differential expression of influx (hOCT1) and efflux (MDR1) transporters may be a critical determinant of intracellular drug levels and, hence, resistance to imatinib.
    Blood 01/2005; 104(12):3739-45. · 9.78 Impact Factor
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    Blood 05/2004; 103(8):3245. · 9.78 Impact Factor
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    ABSTRACT: Real-time quantitative reverse transcription-polymerase chain reaction (Q-RT-PCR) is increasingly used to monitor responses in chronic myeloid leukaemia (CML). The peripheral blood BCR-ABL/ABL ratio, as assessed by Q-RT-PCR, has been shown to correlate with the contemporary cytogenetic response in patients receiving imatinib (Glivec, Gleevec). We have used Q-RT-PCR to monitor the early molecular response to 4 weeks and 3 months of imatinib therapy, in 47 patients with established CML. After 4 weeks of imatinib therapy, patients whose BCR-ABL/ABL ratio had fallen to less than 50% that of baseline had a significantly higher probability of achieving a major cytogenetic response after 6 months of therapy, when compared with those whose ratio did not fall by this amount (P < 0.001). Similarly, patients whose ratio at 3 months was less than 10% of that at baseline had a significantly higher probability of achieving a major cytogenetic remission at 6 months (P < 0.001). Patients who achieved these falls in their BCR-ABL/ABL ratio at either 4 weeks or 3 months had a superior progression-free survival at a median follow-up of 16.5 months (P = 0.01 and 0.003 respectively). These effects were independent of patient age and disease stage. The occurrence of peripheral blood cytopenias sufficiently severe to interrupt therapy was unrelated to progression-free survival. In conclusion, the data suggest that the early trend in the BCR-ABL/ABL ratio may be clinically useful for the early identification of patients destined to fare poorly on imatinib.
    British Journal of Haematology 03/2003; 120(6):990-9. · 4.94 Impact Factor
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    ABSTRACT: Imatinib mesylate (trade name Glivec or Gleevec) is emerging as an important therapy in the management of chronic myeloid leukaemia (CML). It is clinically useful to monitor the cytogenetic response to imatinib, although frequent marrow examinations are inconvenient. We have used serial real-time reverse transcription-polymerase chain reaction (RT-PCR) to monitor the ratio of peripheral blood BCR-ABL to normal ABL transcripts in 43 patients receiving imatinib, and compared the results to concurrent conventional bone marrow (BM) cytogenetics. After 6 months of treatment, 13 cases were complete cytogenetic responders, defined as all BM metaphases negative for the Philadelphia (Ph) chromosome. In these patients, the BCR-ABL/ABL ratio was less than 0.08%. Six cases achieved a partial cytogenetic response (1-35% Ph-positive BM metaphases) and their BCR-ABL/ABL ratio was between 0.08 and 10%. In total, 24 cases were cytogenetic non-responders, and their BCR-ABL/ABL ratio exceeded 11%. The data suggested that the 6-month BCR-ABL/ABL ratio may reliably predict the contemporary marrow cytogenetic response. It was concluded that serial real-time RT-PCR may offer a convenient surrogate assessment of the marrow cytogenetic response to imatinib therapy in CML.
    British Journal of Haematology 10/2002; 118(3):771-7. · 4.94 Impact Factor

Publication Stats

857 Citations
138.62 Total Impact Points

Institutions

  • 2005–2014
    • University of Liverpool
      • Department of Molecular and Clinical Cancer Medicine
      Liverpool, England, United Kingdom
  • 2002–2013
    • Royal Liverpool and Broadgreen University Hospitals NHS Trust
      • Department of Haematology
      Liverpool, England, United Kingdom