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16 results on '"Johnson, Gillian G."'

2. Supplementary Figures 1-3, Tables 1-3 from Functional Analysis of the ATM-p53-p21 Pathway in the LRF CLL4 Trial: Blockade at the Level of p21 Is Associated with Short Response Duration

Author

Lin, Ke, primary, Adamson, Janet, primary, Johnson, Gillian G., primary, Carter, Anthony, primary, Oates, Melanie, primary, Wade, Rachel, primary, Richards, Sue, primary, Gonzalez, David, primary, Matutes, Estella, primary, Dearden, Claire, primary, Oscier, David G., primary, Catovsky, Daniel, primary, and Pettitt, Andrew R., primary

Published
2023
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9. Total Proteome Analysis Identifies Migration Defects As a Major Pathogenetic Factor in IGHV-Unmutated Chronic Lymphocytic Leukemia

Author

Eagle, Gina L, primary, Jenkins, Rosalind E, additional, Till, Kathleen J, additional, Puthen, Jithesh, additional, Lin, Ke, additional, Johnson, Gillian G, additional, Oates, Melanie, additional, Park, Kevin, additional, Kitteringham, Neil R, additional, Zhuang, Jianguo, additional, and Pettitt, Andrew R, additional

Published
2014
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10. The gene expression signature associated with TP53 mutation/deletion in chronic lymphocytic leukaemia is dominated by the under‐expression of TP53 and other genes on chromosome 17p

Author

Lin, Ke, primary, Lane, Brian, additional, Carter, Anthony, additional, Johnson, Gillian G., additional, Onwuazor, Obiageli, additional, Oates, Melanie, additional, Zenz, Thorsten, additional, Stilgenbauer, Stephan, additional, Atherton, Mark, additional, Douglas, Angela, additional, Ebrahimi, Bahram, additional, Sherrington, Paul D., additional, and Pettitt, Andrew R., additional

Published
2012
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11. Functional Analysis of the ATM-p53-p21 Pathway in the LRF CLL4 Trial: Blockade at the Level of p21 Is Associated with Short Response Duration

Author

Lin, Ke, primary, Adamson, Janet, additional, Johnson, Gillian G., additional, Carter, Anthony, additional, Oates, Melanie, additional, Wade, Rachel, additional, Richards, Sue, additional, Gonzalez, David, additional, Matutes, Estella, additional, Dearden, Claire, additional, Oscier, David G., additional, Catovsky, Daniel, additional, and Pettitt, Andrew R., additional

Published
2012
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12. Alemtuzumab in Combination With Methylprednisolone Is a Highly Effective Induction Regimen for Patients With Chronic Lymphocytic Leukemia and Deletion of TP53: Final Results of the National Cancer Research Institute CLL206 Trial

Author

Pettitt, Andrew R., primary, Jackson, Richard, additional, Carruthers, Stacey, additional, Dodd, James, additional, Dodd, Susanna, additional, Oates, Melanie, additional, Johnson, Gillian G., additional, Schuh, Anna, additional, Matutes, Estella, additional, Dearden, Claire E., additional, Catovsky, Daniel, additional, Radford, John A., additional, Bloor, Adrian, additional, Follows, George A., additional, Devereux, Stephen, additional, Kruger, Anton, additional, Blundell, Julie, additional, Agrawal, Samir, additional, Allsup, David, additional, Proctor, Stephen, additional, Heartin, Earnest, additional, Oscier, David, additional, Hamblin, Terry J., additional, Rawstron, Andrew, additional, and Hillmen, Peter, additional

Published
2012
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14. CYP2B6*6is an independent determinant of inferior response to fludarabine plus cyclophosphamide in chronic lymphocytic leukemia

Author

Johnson, Gillian G., Lin, Ke, Cox, Trevor F., Oates, Melanie, Sibson, David R., Eccles, Richard, Lloyd, Bryony, Gardiner, Laura-Jayne, Carr, Daniel F., Pirmohamed, Munir, Strefford, Jonathan C., Oscier, David G., Gonzalez de Castro, David, Else, Monica, Catovsky, Daniel, and Pettitt, Andrew R.

Abstract

Fludarabine plus cyclophosphamide (FC) is the chemotherapy backbone of modern chronic lymphocytic leukemia (CLL) treatment. CYP2B6 is a polymorphic cytochrome P450 isoform that converts cyclophosphamide to its active form. This study investigated the possible impact of genetic variation in CYP2B6on response to FC chemotherapy in CLL. Available DNA samples from the LRF CLL4 trial, which compared chlorambucil, fludarabine, and FC, were screened by TaqMan real-time polymerase chain reaction assays for CYP2B6SNPs c.516G>T and c.785A>G, which define the most common variant allele (*6). Among the 455 samples successfully genotyped, 265 (58.2%), 134 (29.5%), and 29 (6.4%) were classified as *1/*1, *1/*6, and *6/*6, respectively. Patients expressing at least one *6allele were significantly less likely to achieve a complete response (CR) after FC (odds ratio 0.27; P= .004) but not chlorambucil or fludarabine. Analysis of individual response indicators confirmed that this inferior response resulted from impaired cytoreduction rather than delayed hemopoietic recovery. Multivariate analysis controlling for age, gender, stage, IGHVmutational status, 11q deletion, and TP53deletion/mutation identified CYP2B6*6and TP53mutation/deletion as the only independent determinants of CR attainment after FC. Our study provides the first demonstration that host pharmacogenetics can influence therapeutic response in CLL. This trial is registered as an International Standard Randomised Control Trial, number NCT 58585610 at www.clinicaltrials.gov.

Published
2013
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16. Akt is activated in chronic lymphocytic leukemia cells and delivers a pro-survival signal: the therapeutic potential of Akt inhibition.

Author

Zhuang J, Hawkins SF, Glenn MA, Lin K, Johnson GG, Carter A, Cawley JC, and Pettitt AR

Subjects
Apoptosis drug effects, Cell Line, Tumor, Cell Survival drug effects, Cell Survival physiology, Clone Cells, Enzyme Activation drug effects, Enzyme Activation physiology, Humans, Indazoles therapeutic use, Indoles therapeutic use, Leukemia, Lymphocytic, Chronic, B-Cell pathology, Proto-Oncogene Proteins c-akt therapeutic use, Signal Transduction drug effects, Apoptosis physiology, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell enzymology, Proto-Oncogene Proteins c-akt antagonists & inhibitors, Proto-Oncogene Proteins c-akt metabolism, Signal Transduction physiology
Abstract

Background: The aims of the present study were to ascertain the activation status of Akt in the primary cells of chronic lymphocytic leukemia and to investigate the effects of specific Akt inhibition on chronic lymphocytic leukemia-cell survival., Design and Methods: Anti-phospho-Akt (Ser473 or Thr308) antibodies and western blotting were used to establish the activation status of Akt. The effects of two different, specific small-molecule inhibitors (A-443654 or Akti-1/2) or small interfering RNA on cell survival and downstream targets of Akt were assessed. Apoptosis was determined by fluorescence-activated cell sorting analysis of phosphatidylserine exposure and by measurement of PARP cleavage. The phosphorylation status of GSK-3 and MDM2, two immediate downstream substrates of Akt, levels of the anti-apoptotic proteins BCL2 and MCL1, and expression of p53 and p21 were all measured by western blotting., Results: Fully activated Akt was demonstrable in all chronic lymphocytic leukemia clones examined (n=26). These results were validated with extensive controls and it was shown that a harsh method of cell extraction is needed for detection of the active enzyme. Specific inhibition of Akt induced extensive apoptosis of chronic lymphocytic leukemia cells, which was associated with both a rapid loss of MCL1 through proteasomal degradation and increased expression of p53. Moreover, the Akt inhibitors, at concentrations that induced extensive apoptosis in chronic lymphocytic leukemia cells, had little or no effect on normal peripheral blood mononuclear cells., Conclusions: Chronic lymphocytic leukemia clones consistently contain activated Akt which plays a pivotal role in maintaining cell survival. Inhibition of the Akt pathway may be of potential value as a novel therapeutic strategy in chronic lymphocytic leukemia.

Published
2010
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