Up-regulation of anti-apoptotic genes confers resistance to the novel anti-leukaemic compound PEP005 in primary AML cells

Peter Hampson, Keqing Wang, Elisabeth Ersvær, Emmet Mccormack, Julia Schüler, Heinz-herbert Fiebig, Bjørn Tore Gjertsen, Øystein Bruserud, Janet M. Lord

Research output: Contribution to journalArticle

Abstract

We showed previously that PEP005 induced apoptosis in leukaemic cell lines and blasts from patients with acute myeloid leukaemia (AML). Here we assess the anti-leukeamic effects of PEP005 in vivo and determine the mechanism of resistance of PEP005 non-responsive cells. We used 2 human xenograft mouse models of AML to assess the anti-leukaemic effects of PEP005 in vivo. Expression microarray analysis of primary AML blasts following treatment with PEP005 was used to determine patterns of gene expression that conferred resistance. PEP005 significantly reduced tumour burden in two human leukaemia mouse xenograft models. We also assessed responsiveness of 33 AML samples to PEP005, with 78% of the samples entering apoptosis at 100nM. Resistance to PEP005 was not restricted to a particular AML subtype. Expression microarray analysis of resistant samples following treatment with PEP005 revealed a significant up regulation of the anti-apoptotic genes Bcl-2A1, Mcl-1, and PHLDA1 which was verified using RT-PCR. We conclude that PEP005 shows broad efficacy against AML subtypes and that up regulation of anti-apoptotic genes underlies resistance to this agent and could be used to screen for patients unlikely to benefit from a therapeutic regime involving PEP005.
Original languageEnglish
Pages (from-to)529-539
JournalOncoscience
Volume1
Issue number8
DOIs
Publication statusPublished - 6 Aug 2014

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Myeloid Cells
Acute Myeloid Leukemia
Up-Regulation
Genes
Microarray Analysis
Heterografts
3-ingenyl angelate
Apoptosis
Tumor Burden
Leukemia
Therapeutics
Gene Expression
Cell Line
Polymerase Chain Reaction

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This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use,
distribution, and reproduction in any medium, provided the original author and source are credited.

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Hampson, P., Wang, K., Ersvær, E., Mccormack, E., Schüler, J., Fiebig, H., ... Lord, J. M. (2014). Up-regulation of anti-apoptotic genes confers resistance to the novel anti-leukaemic compound PEP005 in primary AML cells. Oncoscience, 1(8), 529-539. https://doi.org/10.18632/oncoscience.v1i8
Hampson, Peter ; Wang, Keqing ; Ersvær, Elisabeth ; Mccormack, Emmet ; Schüler, Julia ; Fiebig, Heinz-herbert ; Gjertsen, Bjørn Tore ; Bruserud, Øystein ; Lord, Janet M. / Up-regulation of anti-apoptotic genes confers resistance to the novel anti-leukaemic compound PEP005 in primary AML cells. In: Oncoscience. 2014 ; Vol. 1, No. 8. pp. 529-539.
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abstract = "We showed previously that PEP005 induced apoptosis in leukaemic cell lines and blasts from patients with acute myeloid leukaemia (AML). Here we assess the anti-leukeamic effects of PEP005 in vivo and determine the mechanism of resistance of PEP005 non-responsive cells. We used 2 human xenograft mouse models of AML to assess the anti-leukaemic effects of PEP005 in vivo. Expression microarray analysis of primary AML blasts following treatment with PEP005 was used to determine patterns of gene expression that conferred resistance. PEP005 significantly reduced tumour burden in two human leukaemia mouse xenograft models. We also assessed responsiveness of 33 AML samples to PEP005, with 78{\%} of the samples entering apoptosis at 100nM. Resistance to PEP005 was not restricted to a particular AML subtype. Expression microarray analysis of resistant samples following treatment with PEP005 revealed a significant up regulation of the anti-apoptotic genes Bcl-2A1, Mcl-1, and PHLDA1 which was verified using RT-PCR. We conclude that PEP005 shows broad efficacy against AML subtypes and that up regulation of anti-apoptotic genes underlies resistance to this agent and could be used to screen for patients unlikely to benefit from a therapeutic regime involving PEP005.",
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Hampson, P, Wang, K, Ersvær, E, Mccormack, E, Schüler, J, Fiebig, H, Gjertsen, BT, Bruserud, Ø & Lord, JM 2014, 'Up-regulation of anti-apoptotic genes confers resistance to the novel anti-leukaemic compound PEP005 in primary AML cells', Oncoscience, vol. 1, no. 8, pp. 529-539. https://doi.org/10.18632/oncoscience.v1i8

Up-regulation of anti-apoptotic genes confers resistance to the novel anti-leukaemic compound PEP005 in primary AML cells. / Hampson, Peter; Wang, Keqing; Ersvær, Elisabeth; Mccormack, Emmet; Schüler, Julia; Fiebig, Heinz-herbert; Gjertsen, Bjørn Tore; Bruserud, Øystein; Lord, Janet M.

In: Oncoscience, Vol. 1, No. 8, 06.08.2014, p. 529-539.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Up-regulation of anti-apoptotic genes confers resistance to the novel anti-leukaemic compound PEP005 in primary AML cells

AU - Hampson, Peter

AU - Wang, Keqing

AU - Ersvær, Elisabeth

AU - Mccormack, Emmet

AU - Schüler, Julia

AU - Fiebig, Heinz-herbert

AU - Gjertsen, Bjørn Tore

AU - Bruserud, Øystein

AU - Lord, Janet M.

N1 - This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2014/8/6

Y1 - 2014/8/6

N2 - We showed previously that PEP005 induced apoptosis in leukaemic cell lines and blasts from patients with acute myeloid leukaemia (AML). Here we assess the anti-leukeamic effects of PEP005 in vivo and determine the mechanism of resistance of PEP005 non-responsive cells. We used 2 human xenograft mouse models of AML to assess the anti-leukaemic effects of PEP005 in vivo. Expression microarray analysis of primary AML blasts following treatment with PEP005 was used to determine patterns of gene expression that conferred resistance. PEP005 significantly reduced tumour burden in two human leukaemia mouse xenograft models. We also assessed responsiveness of 33 AML samples to PEP005, with 78% of the samples entering apoptosis at 100nM. Resistance to PEP005 was not restricted to a particular AML subtype. Expression microarray analysis of resistant samples following treatment with PEP005 revealed a significant up regulation of the anti-apoptotic genes Bcl-2A1, Mcl-1, and PHLDA1 which was verified using RT-PCR. We conclude that PEP005 shows broad efficacy against AML subtypes and that up regulation of anti-apoptotic genes underlies resistance to this agent and could be used to screen for patients unlikely to benefit from a therapeutic regime involving PEP005.

AB - We showed previously that PEP005 induced apoptosis in leukaemic cell lines and blasts from patients with acute myeloid leukaemia (AML). Here we assess the anti-leukeamic effects of PEP005 in vivo and determine the mechanism of resistance of PEP005 non-responsive cells. We used 2 human xenograft mouse models of AML to assess the anti-leukaemic effects of PEP005 in vivo. Expression microarray analysis of primary AML blasts following treatment with PEP005 was used to determine patterns of gene expression that conferred resistance. PEP005 significantly reduced tumour burden in two human leukaemia mouse xenograft models. We also assessed responsiveness of 33 AML samples to PEP005, with 78% of the samples entering apoptosis at 100nM. Resistance to PEP005 was not restricted to a particular AML subtype. Expression microarray analysis of resistant samples following treatment with PEP005 revealed a significant up regulation of the anti-apoptotic genes Bcl-2A1, Mcl-1, and PHLDA1 which was verified using RT-PCR. We conclude that PEP005 shows broad efficacy against AML subtypes and that up regulation of anti-apoptotic genes underlies resistance to this agent and could be used to screen for patients unlikely to benefit from a therapeutic regime involving PEP005.

U2 - 10.18632/oncoscience.v1i8

DO - 10.18632/oncoscience.v1i8

M3 - Article

VL - 1

SP - 529

EP - 539

IS - 8

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