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40 results on '"Eadie, Laura N."'

6. Reproducible Bioinformatics Analysis Workflows for Detecting IGH Gene Fusions in B-Cell Acute Lymphoblastic Leukaemia Patients

Author

Thomson, Ashlee J., primary, Rehn, Jacqueline A., additional, Heatley, Susan L., additional, Eadie, Laura N., additional, Page, Elyse C., additional, Schutz, Caitlin, additional, McClure, Barbara J., additional, Sutton, Rosemary, additional, Dalla-Pozza, Luciano, additional, Moore, Andrew S., additional, Greenwood, Matthew, additional, Kotecha, Rishi S., additional, Fong, Chun Y., additional, Yong, Agnes S. M., additional, Yeung, David T., additional, Breen, James, additional, and White, Deborah L., additional

Published
2023
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9. Case Report: Rare IKZF1 Gene Fusions Identified in Neonate with Congenital KMT2A-Rearranged Acute Lymphoblastic Leukemia

Author

Eadie, Laura N., primary, Rehn, Jacqueline A., additional, Breen, James, additional, Osborn, Michael P., additional, Jessop, Sophie, additional, Downes, Charlotte E. J., additional, Heatley, Susan L., additional, McClure, Barbara J., additional, Yeung, David T., additional, Revesz, Tamas, additional, Saxon, Benjamin, additional, and White, Deborah L., additional

Published
2023
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11. Case Report: Precision Medicine Target Revealed by In Vitro Modeling of Relapsed, Refractory Acute Lymphoblastic Leukemia From a Child With Neurofibromatosis

Author

Heatley, Susan L., primary, Page, Elyse C., additional, Eadie, Laura N., additional, McClure, Barbara J., additional, Rehn, Jacqueline, additional, Yeung, David T., additional, Osborn, Michael, additional, Revesz, Tamas, additional, Kirby, Maria, additional, and White, Deborah L., additional

Published
2022
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19. Exploring the oncogenic and therapeutic target potential of the MYB-TYK2fusion gene in B-cell acute lymphoblastic leukemia

Author

Shirazi, Paniz Tavakoli, Eadie, Laura N., Heatley, Susan L., Page, Elyse C., François, Maxime, Hughes, Timothy P., Yeung, David, and White, Deborah L.

Abstract

TYK2-rearrangements have recently been identified in high-risk acute lymphoblastic leukemia (HR-ALL) cases and are associated with poor outcome. Current understanding of the leukemogenic potential and therapeutic targetability of activating TYK2alterations in the ALL setting is unclear, thus further investigations are warranted. Consequently, we developed in vitro, and for the first time, in vivo models of B-cell ALL from a patient harboring the MYB-TYK2fusion gene. These models revealed JAK/STAT signaling activation and the oncogenic potential of the MYB-TYK2fusion gene in isolation. High throughput screening identified the HDAC inhibitor, vorinostat and the HSP90 inhibitor, tanespimycin plus the JAK inhibitor, cerdulatinib as the most effective agents against cells expressing the MYB-TYK2alteration. Evaluation of vorinostat and cerdulatinib in pre-clinical models of MYB-TYK2-rearranged ALL demonstrated that both drugs exhibited anti-leukemic effects and reduced the disease burden in treated mice. Importantly, these findings indicate that activating TYK2alterations can function as driver oncogenes rather than passenger or secondary events in disease development. In addition, our data provide evidence for use of vorinostat and cerdulatinib in the treatment regimens of patients with this rare yet aggressive type of high-risk ALL that warrants further investigation in the clinical setting.

Published
2022
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23. High Risk Genomic Alterations Identified at the Time of Diagnosis Are Strongly Associated with MRD and Subsequent Poor Outcomes in AYA ALL Patients Treated on a Pediatric Inspired Chemotherapy Regimen

Author

Yeung, David T, primary, Greenwood, Matthew, additional, Rhen, Jacqueline, additional, Heatley, Susan L, additional, McClure, Barbara, additional, Eadie, Laura N, additional, Breen, Jimmy, additional, Schutz, Caitlin Schutz, additional, Trahair, Toby N, additional, Wei, Andrew H., additional, Dalla-Pozza, Luciano, additional, Sutton, Rosemary, additional, Bradstock, Kenneth F, additional, Osborn, Michael Philip, additional, and White, Deborah L., additional

Published
2019
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24. HMGN1plays a significant role in CRLF2driven Down Syndrome leukemia and provides a potential therapeutic target in this high-risk cohort

Author

Page, Elyse C., Heatley, Susan L., Eadie, Laura N., McClure, Barbara J., de Bock, Charles E., Omari, Sofia, Yeung, David T., Hughes, Timothy P., Thomas, Paul Q., and White, Deborah L.

Abstract

The genetic basis of the predisposition for Down Syndrome (DS) patients to develop cytokine receptor-like factor 2 rearranged (CRLF2r) acute lymphoblastic leukemia (ALL) is currently unknown. Genes located on chromosome 21 and expressed in hematopoietic cells are likely candidates for investigation of CRLF2rDS-ALL pathogenesis. We explored the high-mobility group nucleosome-binding protein 1 (HMGN1), located in the DS critical region, in an inducible CRISPR/Cas9 knockout (KO) xenograft model to assess the effect of HMGN1loss of function on the leukemic burden. We demonstrated HMGN1KO-mitigated leukemic phenotypes including hepatosplenomegaly, thrombocytopenia, and anemia, commonly observed in leukemia patients, and significantly increased survival in vivo. HMGN1overexpression in murine stem cells and Ba/F3 cells in vitro, in combination with P2RY8-CRLF2, resulted in cytokine-independent transformation and upregulation of cell signaling pathways associated with leukemic development. Finally, in vitro screening demonstrated successful targeting of P2RY8-CRLF2and HMGN1co-expressing cell lines and patient samples with fedratinib (JAK2 inhibitor), and GSK-J4 (demethylase inhibitor) in combination. Together, these data provide critical insight into the development and persistence of CRLF2rDS-ALL and identify HMGN1as a potential therapeutic target to improve outcomes and reduce toxicity in this high-risk cohort of young patients.

Published
2022
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35. Degree of kinase inhibition achieved in vitro by imatinib and nilotinib is decreased by high levels of ABCB1 but not ABCG2.

Author

Eadie, Laura N., Saunders, Verity A., Hughes, Timothy P., and White, Deborah L.

Subjects
*CHRONIC myeloid leukemia, *IMATINIB, *NILOTINIB, *ATP-binding cassette transporters, *KINASE inhibitors
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 (IC50) compared with parental K562 cells for imatinib (IC50IM; 9 µM to 19 µM, p = 0.002) and nilotinib (IC50NIL; 345 nM to 620 nM, p = 0.013). This difference was abrogated by ABCB1 inhibitors. However, overexpression of ABCG2 did not significantly increase IC50IM or IC50NIL or significantly decrease IC50 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. [ABSTRACT FROM AUTHOR]

Published
2013
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37. The Allosteric Inhibitor ABL001 Is Susceptible to Resistance in VitroMediated By Overexpression of the Drug Efflux Transporters ABCB1 and ABCG2

Author

Eadie, Laura N, Saunders, Verity A, Leclercq, Tamara M, Branford, Susan, White, Deborah L, and Hughes, Timothy P.

Abstract

Tyrosine Kinase Inhibitors (TKIs) result in excellent responses in Chronic Myeloid Leukaemia (CML) patients. However, secondary resistance is observed in ~35% of patients, mostly due to Bcr-Abl kinase domain (KD) mutations. Overexpression of the efflux transporter ABCB1 is a known mediator of primary resistance to imatinib (IM) and nilotinib (NIL). ABL001, a potent allosteric inhibitor, binds to the myristate pocket of the Bcr-Abl KD. In this study, we modelled ABL001 resistance in vitrowith particular focus on ABCB1 and ABCG2.

Published
2015
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39. HMGN1 plays a significant role in CRLF2 driven Down Syndrome leukemia and provides a potential therapeutic target in this high-risk cohort

Author

David T Yeung, Timothy P. Hughes, Deborah L. White, Sofia Omari, Paul Q. Thomas, Elyse C. Page, Susan L. Heatley, Charles E. de Bock, Laura N Eadie, Barbara J. McClure, Page, Elyse C, Heatley, Susan L, Eadie, Laura N, McClure, Barbara J, de Bock, Charles E, Omari, Sofia, Yeung, David T, Hughes, Timothy P, Thomas, Paul Q, and White, Deborah L

Subjects
CRLF2r, Cancer Research, Down syndrome, medicine.medical_treatment, leukemia, Hepatosplenomegaly, acute lymphoblastic leukemia, Biology, medicine.disease, Haematopoiesis, Leukemia, Cytokine, Downregulation and upregulation, HMGN1, high-mobility group nucleosome-binding protein 1, Genetics, medicine, Cancer research, cytokine receptor-like factor 2 rearranged, Down Syndrome, medicine.symptom, Stem cell, Chromosome 21, Molecular Biology, HMGN1 Protein
Abstract

Refereed/Peer-reviewed The genetic basis of the predisposition for Down Syndrome (DS) patients to develop cytokine receptor-like factor 2 rearranged (CRLF2r) acute lymphoblastic leukemia (ALL) is currently unknown. Genes located on chromosome 21 and expressed in hematopoietic cells are likely candidates for investigation of CRLF2r DS-ALL pathogenesis. We explored the high-mobility group nucleosome-binding protein 1 (HMGN1), located in the DS critical region, in an inducible CRISPR/Cas9 knockout (KO) xenograft model to assess the effect of HMGN1 loss of function on the leukemic burden. We demonstrated HMGN1 KO-mitigated leukemic phenotypes including hepatosplenomegaly, thrombocytopenia, and anemia, commonly observed in leukemia patients, and significantly increased survival in vivo. HMGN1 overexpression in murine stem cells and Ba/F3 cells in vitro, in combination with P2RY8-CRLF2, resulted in cytokine-independent transformation and upregulation of cell signaling pathways associated with leukemic development. Finally, in vitro screening demonstrated successful targeting of P2RY8-CRLF2 and HMGN1 co-expressing cell lines and patient samples with fedratinib (JAK2 inhibitor), and GSK-J4 (demethylase inhibitor) in combination. Together, these data provide critical insight into the development and persistence of CRLF2r DS-ALL and identify HMGN1 as a potential therapeutic target to improve outcomes and reduce toxicity in this high-risk cohort of young patients.

Published
2021

40. The new allosteric inhibitor asciminib is susceptible to resistance mediated by ABCB1 and ABCG2 overexpression in vitro

Author

Susan Branford, Timothy P. Hughes, Verity A Saunders, Deborah L. White, Laura N Eadie, Eadie, Laura N, Saunders, Verity A, Branford, Susan, White, Deborah L, and Hughes, Timothy P

Subjects
0301 basic medicine, asciminib, ABCG2, ABL001, Imatinib, ABCB1, Biology, Pharmacology, In vitro, Dasatinib, resistance, 03 medical and health sciences, 030104 developmental biology, 0302 clinical medicine, Oncology, Nilotinib, Cell culture, 030220 oncology & carcinogenesis, hemic and lymphatic diseases, medicine, Doxorubicin, Efflux, medicine.drug, K562 cells, Research Paper
Abstract

Asciminib (previously ABL001), which binds the myristate-binding pocket of the Bcr-Abl kinase domain, is in phase I clinical trials as monotherapy and in combination with imatinib, nilotinib and dasatinib for the treatment of patients with refractory CML or Ph+ ALL. Asciminib sensitivity was evaluated in asciminib naïve BCR-ABL1+ cell lines K562 (negligible ABCB1/ABCG2 expression), K562-Dox (ABCB1-overexpressing through doxorubicin exposure) and K562-ABCG2 (ABCG2 overexpression via transduction) with results demonstrating asciminib efflux by both ABCB1 and ABCG2 transporters. K562-Dox and K562-ABCG2 cells demonstrated increased LD50 asciminib vs K562 control cells: 256 and 299 nM respectively vs 24 nM, p < 0.001. Sensitivity was completely restored with specific inhibitors cyclosporine (ABCB1) and Ko143 (ABCG2): K562-Dox LD50 asciminib+cyclosporine = 13 nM, K562-ABCG2 LD50 asciminib+Ko143 = 15 nM (p < 0.001). When asciminib resistance was modelled in vitro, ABCB1 and ABCG2 overexpression was integral in the development of asciminib resistance. In K562 asciminib-resistant cells, ABCG2 expression increased prior to BCR-ABL1 overexpression and remained high (up to 7.6-fold greater levels in resistant vs control cells, p < 0.001). K562-Dox asciminib-resistant cells had increased ABCB1 expression (2.1-fold vs control cells p = 0.0033). KU812 asciminib-resistant cells overexpressed ABCB1 (5.4-fold increase, p < 0.001) and ABCG2 (6-fold increase, p < 0.001) before emergence of a novel myristate-binding pocket mutation (F497L). In all three cell lines, asciminib resistance was reversible upon chemical inhibition of ABCB1, ABCG2 or both (p < 0.001). When K562 asciminib-resistant cells were treated with asciminib in combination with clinically achievable doses of either imatinib or nilotinib, reversal of the resistance phenotype was also observed (p < 0.01). Overexpression of efflux transporters will likely be an important pathway for asciminib resistance in the clinical setting. Given the lack of evidence for ABCG2-mediated transport of nilotinib or imatinib at clinically relevant concentrations, our data provide an additional rationale for using asciminib in combination with either TKI. Refereed/Peer-reviewed

Published
2018

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