title: Up-regulation of anti-apoptotic genes confers resistance to the novel anti-leukaemic compound PEP005 in primary AML cells.
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.
authors.affiliation: School of Immunity and Infection, University of Birmingham, Birmingham, B15 2TT, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Hampson
authors.affiliation: Department of Biosciences, University of Aston, Birmingham, B4 7ET.
authors.forename: Keqing
authors.initials: K
authors.lastname: Wang
authors.affiliation: Institute of Medicine, University of Bergen, Bergen, NO-5020, Norway.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Ersvær
authors.affiliation: Institute of Medicine, University of Bergen, Bergen, NO-5020, Norway.
authors.forename: Emmet
authors.initials: E
authors.lastname: McCormack
authors.affiliation: Oncotest GmbH, 79801 Freiburg, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Schüler
authors.affiliation: Oncotest GmbH, 79801 Freiburg, Germany.
authors.forename: Heinz-Herbert
authors.initials: HH
authors.lastname: Fiebig
authors.affiliation: Institute of Medicine, University of Bergen, Bergen, NO-5020, Norway.
authors.forename: Bjørn Tore
authors.initials: BT
authors.lastname: Gjertsen
authors.affiliation: Institute of Medicine, University of Bergen, Bergen, NO-5020, Norway.
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Bruserud
authors.affiliation: School of Immunity and Infection, University of Birmingham, Birmingham, B15 2TT, UK.
authors.forename: Janet M
authors.initials: JM
authors.lastname: Lord
keywords: AML; PEP005; PKC; anti-apoptotic; xenograft model