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Jahrestagung der ­Deutschen, Österreichischen und ­Schweizerischen ­Gesellschaften für Hämatologie und ­Medizinische Onkologie. Abstract P500: Suppression of c-Myc by PAM pathway inhibition and ATRA treatment for therapeutic gain in acute myeloid leukemia.

Schenk, Tino, Stengel, Sven, Kahl, Melanie, Rodriguez, Ana, Perez, Aymee, Swords, Ronan T, Petrie, Kevin and Zelent, Arthur (2016) Jahrestagung der ­Deutschen, Österreichischen und ­Schweizerischen ­Gesellschaften für Hämatologie und ­Medizinische Onkologie. Abstract P500: Suppression of c-Myc by PAM pathway inhibition and ATRA treatment for therapeutic gain in acute myeloid leukemia. Oncology Research and Treatment, 39 (3). p. 145. ISSN 2296-5270

Item Type: Article

Abstract

Introduction: Defects in the proto-oncogene c-Myc have been widely implicated in the initiation and maintenance of acute myeloid leukemia (AML), however, c-Myc has been an elusive therapeutic target for drug development. In this study, we sought to target aberrant c-Myc expression by inhibition of the PAM signaling pathway in conjunction with all-trans retinoic acid (ATRA) as a strategy to reduce stem cell potential as well as to induce growth arrest, differentiation and apoptosis in AML cells. Methods: Small molecule inhibitors of PI3K (ZSTK474), mTOR (WYE- 125132) and PI3K/mTOR (NVP-BEZ235, dactolisib) where used alone or in combination with ATRA to treat AML cell lines and primary patient samples. Colony formation potential, cell growth, cell cycle arrest, differentiation and apoptosis were analyzed. c-Myc levels were monitored by qPCR and immunoblotting. Global gene expression profiling was conducted using Affymetrix GeneChip® ST Arrays.
Results: PI3K and mTOR inhibition by ZSTK474 or WYE-125132 respectively, induced cell cycle arrest at low nanomolar concentrations in AML cell lines and primary patient samples. The dual PI3K/mTOR inhibitor NVP-BEZ235 was the most potent PAM inhibitor tested. Addition of ATRA further augmented the anti-leukemic effects of PAM inhibitors in vitro. Co-treatment lead to reduced colony formation capacity as well as cell cycle arrest, differentiation and programmed cell death. We observed a rapid down regulation of c-Myc following treatment with NVP-BEZ235 via impaired translation, destabilization and enhanced degradation. ATRA treatment caused transcriptional and translational repression. NVP-BEZ235 combined with ATRA produced maximal c-Myc suppression and the greatest anti-leukemic effects. Detailed analysis of transcriptome changes in MV4-11 cells following treatment with NVP-BEZ235 and ATRA, revealed that both agents regulated the same biologic pathways, but acted on different gene sets within these pathways. Conclusions: Here we present a novel multi-target approach to suppress aberrant c-Myc levels in AML. While inhibition of the PAM pathway leads to inhibition of c-Myc translation, destabilization and degradation, supplementary treatment with ATRA can further decrease c-Myc levels by inhibition of its transcription as well as translation. These data support the clinical investigation of ATRA combined with PAM inhibitors especially in AML patient with high c-Myc activity.

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More Information

Depositing User: Kevin Petrie

Identifiers

Item ID: 15824
Identification Number: https://doi.org/10.1159/000449050
ISSN: 2296-5270
URI: http://sure.sunderland.ac.uk/id/eprint/15824
Official URL: http://dx.doi.org/10.1159/000449050

Users with ORCIDS

ORCID for Kevin Petrie: ORCID iD orcid.org/0000-0002-9805-9152

Catalogue record

Date Deposited: 22 Mar 2023 15:49
Last Modified: 22 Mar 2023 15:49

Contributors

Author: Kevin Petrie ORCID iD
Author: Tino Schenk
Author: Sven Stengel
Author: Melanie Kahl
Author: Ana Rodriguez
Author: Aymee Perez
Author: Ronan T Swords
Author: Arthur Zelent

University Divisions

Faculty of Health Sciences and Wellbeing > School of Medicine

Subjects

Sciences > Biomedical Sciences
Sciences

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