ORCID Profile
0000-0003-1912-7602
Current Organisation
South Australian Health and Medical Research Institute
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Publisher: American Association for Cancer Research (AACR)
Date: 15-06-2008
DOI: 10.1158/1078-0432.CCR-07-5095
Abstract: Purpose: The organic cation transporter OCT-1 mediates active transport of imatinib. We recently showed that low OCT-1 activity is a major contributor to suboptimal response in chronic myeloid leukemia (CML) patients treated with imatinib. The relevance of OCT-1 activity and efflux pumps in determining intracellular uptake and retention (IUR) of dasatinib was assessed. Experimental Design: The effect of OCT inhibitors on [14C]dasatinib and [14C]imatinib IUR was compared using peripheral blood mononuclear cells from newly diagnosed CML patients. The role of efflux transporters was studied using ABCB1- and ABCG2-overexpressing cell lines and relevant inhibitors. Results: Unlike imatinib, there was no significant difference in the dasatinib IUR at 37°C and 4°C (P = 0.8), and OCT-1 inhibitors including prazosin did not reduce dasatinib IUR significantly. In CML mononuclear cells, prazosin inhibitable IUR was significantly higher for imatinib than dasatinib (6.38 versus 1.48 ng/200,000 cells P = 0.002 n = 11). Patients with high OCT-1 activity based on their imatinib uptake had IC50dasatinib values equivalent to patients with low OCT-1 activity. Dasatinib IUR was significantly lower in ABCB1-overexpressing cell lines compared with parental cell lines (P & 0.05). PSC833 (ABCB1 inhibitor) significantly increased the dasatinib IUR (P & 0.05) and reduced IC50dasatinib (from 100 to 8 nmol/L) in K562-DOX cell line. The ABCG2 inhibitor Ko143 significantly increased dasatinib IUR in ABCG2-overexpressing cell lines and reduced IC50dasatinib. Conclusion: Unlike imatinib, dasatinib cellular uptake is not significantly affected by OCT-1 activity, so that expression and function of OCT-1 is unlikely to affect response to dasatinib. Dasatinib is a substrate of both efflux proteins, ABCB1 and ABCG2.
Publisher: MDPI AG
Date: 19-01-2023
Abstract: Chromosomal rearrangements involving the KMT2A gene occur frequently in acute lymphoblastic leukaemia (ALL). KMT2A-rearranged ALL (KMT2Ar ALL) has poor long-term survival rates and is the most common ALL subtype in infants less than 1 year of age. KMT2Ar ALL frequently occurs with additional chromosomal abnormalities including disruption of the IKZF1 gene, usually by exon deletion. Typically, KMT2Ar ALL in infants is accompanied by a limited number of cooperative le-sions. Here we report a case of aggressive infant KMT2Ar ALL harbouring additional rare IKZF1 gene fusions. Comprehensive genomic and transcriptomic analyses were performed on sequential s les. This report highlights the genomic complexity of this particular disease and describes the novel gene fusions IKZF1::TUT1 and KDM2A::IKZF1.
Publisher: Springer Science and Business Media LLC
Date: 23-03-2018
Publisher: Springer Science and Business Media LLC
Date: 09-10-2014
Abstract: The efflux transporters adenosine triphosphate (ATP)-binding cassette (ABC)B1 and ABCG2 have been demonstrated to interact with the tyrosine kinase inhibitors (TKIs) imatinib, nilotinib, and dasatinib. However, although some studies conclude that TKIs are substrates of one or both transporters, other studies demonstrate only an inhibitory function. This variation is probably due to differences in the concentration of TKIs assayed and the experimental systems used. This article examines the evidence for clinically relevant interactions between three currently approved TKIs and ABCB1/ABCG2.
Publisher: Impact Journals, LLC
Date: 03-02-2018
Publisher: Springer Science and Business Media LLC
Date: 11-02-2010
DOI: 10.1038/LEU.2010.7
Publisher: Elsevier BV
Date: 08-2021
Publisher: IOP Publishing
Date: 09-2014
Publisher: Informa UK Limited
Date: 21-08-2013
DOI: 10.3109/10428194.2012.715345
Abstract: Imatinib and nilotinib interact with ABCB1 and ABCG2. However, whether they are substrates or inhibitors is a source of conjecture. Here, in vitro, Bcr-Abl kinase inhibition was used to elucidate the impact of ABCB1/ABCG2 overexpression on imatinib and nilotinib transport. High levels of ABCB1 protein in K562-Dox cells resulted in a significantly increased 50% inhibitory concentration (IC(50)) compared with parental K562 cells for imatinib (IC(50)(IM) 9 µM to 19 µM, p = 0.002) and nilotinib (IC(50)(NIL) 345 nM to 620 nM, p = 0.013). This difference was abrogated by ABCB1 inhibitors. However, overexpression of ABCG2 did not significantly increase IC(50)(IM) or IC(50)(NIL) or significantly decrease IC(50) upon ABCG2 inhibition. Inhibition of ABCB1 but not ABCG2 resulted in a substantial increase in intracellular nilotinib when used at 150 nM but no increase when used at 2 µM. Imatinib and nilotinib appear to be transported by ABCB1 but do not interact strongly with ABCG2. Furthermore, ABCB1 efflux of nilotinib may be concentration-dependent with transport occurring at clinically relevant concentrations.
Publisher: Public Library of Science (PLoS)
Date: 18-08-2016
Publisher: Springer Science and Business Media LLC
Date: 03-12-2020
DOI: 10.1038/S41416-019-0647-7
Abstract: Despite advances in the management of acute lymphoblastic leukaemia (ALL), current regimens fail to significantly transform outcomes for patients with high-risk subtypes. Advances in genomic analyses have identified novel lesions including mutations in genes that encode chromatin modifiers and those that influence cytokine and kinase signalling, rendering many of these alterations potentially targetable by tyrosine kinase and epigenetic inhibitors currently in clinical use. Although specific genomic lesions, gene expression patterns, and immunophenotypic profiles have been associated with specific clinical outcomes in some cancers, the application of precision medicine approaches based on these data has been slow. This approach is complicated by the reality that patients often harbour multiple mutations, and in many cases, the precise functional significance and interaction of these mutations in driving leukaemia and drug responsiveness/resistance remains unknown. Given that signalling pathways driving leukaemic pathogenesis could plausibly result from the co-existence of specific lesions and the resultant perturbation of protein interactions, the use of combined therapeutics that target multiple aberrant pathways, according to an in idual’s mutational profile, might improve outcomes and lower a patient’s risk of relapse. Here we outline the genomic alterations that occur in T cell ALL (T-ALL) and early T cell precursor (ETP)-ALL and review studies highlighting the possible effects of co-occurring lesions on leukaemogenesis and drug response.
Publisher: Elsevier BV
Date: 2019
Publisher: MDPI AG
Date: 26-09-2023
Publisher: Springer Science and Business Media LLC
Date: 02-12-2017
DOI: 10.1038/LEU.2016.335
Publisher: Public Library of Science (PLoS)
Date: 17-10-2022
DOI: 10.1371/JOURNAL.PGEN.1010300
Abstract: RNA-sequencing (RNA-seq) efforts in acute lymphoblastic leukaemia (ALL) have identified numerous prognostically significant genomic alterations which can guide diagnostic risk stratification and treatment choices when detected early. However, integrating RNA-seq in a clinical setting requires rapid detection and accurate reporting of clinically relevant alterations. Here we present RaScALL, an implementation of the k-mer based variant detection tool km , capable of identifying more than 100 prognostically significant lesions observed in ALL, including gene fusions, single nucleotide variants and focal gene deletions. We compared genomic alterations detected by RaScALL and those reported by alignment-based de novo variant detection tools in a study cohort of 180 Australian patient s les. Results were validated using 100 patient s les from a published North American cohort. RaScALL demonstrated a high degree of accuracy for reporting subtype defining genomic alterations. Gene fusions, including difficult to detect fusions involving EPOR and DUX4 , were accurately identified in 98% of reported cases in the study cohort (n = 164) and 95% of s les (n = 63) in the validation cohort. Pathogenic sequence variants were correctly identified in 75% of tested s les, including all cases involving subtype defining variants PAX5 p.P80R (n = 12) and IKZF1 p.N159Y (n = 4). Intragenic IKZF1 deletions resulting in aberrant transcript isoforms were also detectable with 98% accuracy. Importantly, the median analysis time for detection of all targeted alterations averaged 22 minutes per s le, significantly shorter than standard alignment-based approaches. The application of RaScALL enables rapid identification and reporting of previously identified genomic alterations of known clinical relevance.
Publisher: Wiley
Date: 15-08-2020
DOI: 10.1002/GCC.22887
Publisher: Public Library of Science (PLoS)
Date: 31-01-2018
Publisher: Springer Science and Business Media LLC
Date: 16-10-2013
DOI: 10.1038/LEU.2012.295
Publisher: Springer Science and Business Media LLC
Date: 24-06-2017
DOI: 10.1038/LEU.2016.179
Abstract: Tyrosine kinase inhibitor (TKI) therapy results in excellent responses in the majority of patients with chronic myeloid leukaemia. First-line imatinib treatment, with selective switching to nilotinib when patients fail to meet specific molecular targets or for imatinib intolerance, results in excellent overall molecular responses and survival. However, this strategy is less effective in cases of primary imatinib resistance moreover, 25% of patients develop secondary resistance such that 20-35% of patients initially treated with imatinib will eventually experience treatment failure. Early identification of these patients is of high clinical relevance. Since the drug efflux transporter ABCB1 has previously been implicated in TKI resistance, we determined if early increases in ABCB1 mRNA expression (fold change from diagnosis to day 22 of imatinib therapy) predict for patient response. Indeed, patients exhibiting a high fold rise (⩾2.2, n=79) were significantly less likely to achieve early molecular response (BCR-ABL1
Publisher: Informa UK Limited
Date: 02-01-2021
Publisher: Wiley
Date: 31-07-2023
DOI: 10.1111/BJH.19008
Abstract: Donor‐derived haematological neoplasms, in which recipients present with haematological malignancies that have evolved from transplant donor stem cells, have previously been described for myelodysplastic syndrome, myeloproliferative neoplasms, acute myeloid leukaemia and less often, leukaemias of lymphoid origin. Here we describe a rare and complex case of donor‐derived T‐cell acute lymphoblastic leukaemia with a relatively short disease latency of less than 4 years. Through genomic and in vitro analyses, we identified novel mutations in NOTCH1 as well as a novel activating mutation in STAT5B the latter targetable with the clinically available drugs, venetoclax and ruxolitinib.
Location: United States of America
Location: Australia
Location: Australia
Start Date: 2017
End Date: 2019
Funder: Channel 7 Children's Research Foundation
View Funded ActivityStart Date: 2009
End Date: 2012
Funder: Department of Education, Australian Governement
View Funded ActivityStart Date: 2016
End Date: 2017
Funder: Australian-American Fulbright Commission
View Funded ActivityStart Date: 2009
End Date: 2012
Funder: Royal Adelaide Hospital
View Funded ActivityStart Date: 2016
End Date: 2016
Funder: Department of Education, Australian Governement
View Funded ActivityStart Date: 2009
End Date: 2012
Funder: Leukaemia Foundation of Australia
View Funded ActivityStart Date: 2019
End Date: 2021
Funder: Cancer Council South Australia
View Funded ActivityStart Date: 2016
End Date: 2017
Funder: Council for International Exchange of Scholars
View Funded Activity