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Proteome and phosphoproteome changes associated with prognosis in acute myeloid leukemia

Elise Aasebø, Frode S. Berven, Sushma Bartaula-Brevik, Tomasz Stokowy, Randi Hovland, Marc Vaudel, Stein Ove Døskeland, Emmet McCormack, Tanveer S. Batth, View ORCID ProfileJesper V. Olsen, Øystein Bruserud, Frode Selheim, Maria Hernandez-Valladares
doi: https://doi.org/10.1101/796011
Elise Aasebø
1Department of Clinical Science, University of Bergen, Bergen, Norway
2The Proteomics Facility of the University of Bergen (PROBE), University of Bergen, Bergen, Norway
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Frode S. Berven
2The Proteomics Facility of the University of Bergen (PROBE), University of Bergen, Bergen, Norway
3The Department of Biomedicine, University of Bergen, Bergen, Norway
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Sushma Bartaula-Brevik
1Department of Clinical Science, University of Bergen, Bergen, Norway
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Tomasz Stokowy
1Department of Clinical Science, University of Bergen, Bergen, Norway
4Department for Medical Genetics, Haukeland University Hospital, Bergen, Norway
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Randi Hovland
4Department for Medical Genetics, Haukeland University Hospital, Bergen, Norway
5Department of Biological Sciences, University of Bergen, Bergen, Norway
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Marc Vaudel
1Department of Clinical Science, University of Bergen, Bergen, Norway
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Stein Ove Døskeland
3The Department of Biomedicine, University of Bergen, Bergen, Norway
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Emmet McCormack
6Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway
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Tanveer S. Batth
7Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Denmark
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Jesper V. Olsen
7Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Denmark
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  • ORCID record for Jesper V. Olsen
Øystein Bruserud
1Department of Clinical Science, University of Bergen, Bergen, Norway
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Frode Selheim
2The Proteomics Facility of the University of Bergen (PROBE), University of Bergen, Bergen, Norway
3The Department of Biomedicine, University of Bergen, Bergen, Norway
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Maria Hernandez-Valladares
1Department of Clinical Science, University of Bergen, Bergen, Norway
2The Proteomics Facility of the University of Bergen (PROBE), University of Bergen, Bergen, Norway
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  • For correspondence: Maria.Hernandez-Valladares@uib.no
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Abstract

Acute myeloid leukemia (AML) is a hematological cancer that mainly affects the elderly. Although complete remission (CR) is achieved for majority of the patients after induction and consolidation therapies, nearly two-thirds relapse within a short interval. Understanding biological factors that determine relapse has therefore become of major clinical interest in AML. We utilized liquid chromatography tandem mass spectrometry (LC-MS/MS) to identify protein changes and protein phosphorylation events associated with AML relapse in primary cells from 41 AML patients at time of diagnosis. Patients were defined as relapse-free if they had not relapsed within a 5-year clinical follow-up after AML diagnosis. Relapse was associated with increased expression of RNA processing proteins and decreased expression of V-ATPase proteins. We also observed an increase in phosphorylation events catalyzed by cyclin-dependent kinases (CDKs) and casein kinase 2 (CSK2). The biological relevance of the proteome findings was supported by cell proliferation assays using inhibitors of V-ATPase (bafilomycin), CSK2 (CX-4945), CDK4/6 (abemaciclib) and CDK2/7/9 (SNS-032). While bafilomycin preferentially inhibited the cells from relapse patients, the kinase inhibitors were less efficient in these cells. This suggests that therapy against the upregulated kinases also could target the factors inducing their upregulation rather than their activity. In conclusion, our study presents markers that could help predict AML relapse and direct therapeutic strategies.

Footnotes

  • ↵¤ M.H.V. and F.S. share last authorship

  • Key Points

    • V-ATPases and RNA processing proteins are downregulated and upregulated, respectively, in relapse patients

    • Relapse patients show higher activity of CSK2 and CDKs when compared to relapse-free patients

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted October 10, 2019.
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Proteome and phosphoproteome changes associated with prognosis in acute myeloid leukemia
Elise Aasebø, Frode S. Berven, Sushma Bartaula-Brevik, Tomasz Stokowy, Randi Hovland, Marc Vaudel, Stein Ove Døskeland, Emmet McCormack, Tanveer S. Batth, Jesper V. Olsen, Øystein Bruserud, Frode Selheim, Maria Hernandez-Valladares
bioRxiv 796011; doi: https://doi.org/10.1101/796011
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Proteome and phosphoproteome changes associated with prognosis in acute myeloid leukemia
Elise Aasebø, Frode S. Berven, Sushma Bartaula-Brevik, Tomasz Stokowy, Randi Hovland, Marc Vaudel, Stein Ove Døskeland, Emmet McCormack, Tanveer S. Batth, Jesper V. Olsen, Øystein Bruserud, Frode Selheim, Maria Hernandez-Valladares
bioRxiv 796011; doi: https://doi.org/10.1101/796011

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