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Wildschut, Mattheus H. E.; Mena, Julien; Dördelmann, Cyril; van Oostrum, Marc; Hale, Benjamin D.; Settelmeier, Jens; Festl, Yasmin; Lysenko, Veronika; Schürch, Patrick M.; Ring, Alexander; Severin, Yannik; Bader, Michael S.; Pedrioli, Patrick G. A.; Goetze, Sandra; van Drogen, Audrey; Balabanov, Stefan; Skoda, Radek C.; Lopes, Massimo; Wollscheid, Bernd; Theocharides, Alexandre P. A.; Snijder, Berend

Proteogenetic drug response profiling elucidates targetable vulnerabilities of myelofibrosis

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  • Media type: E-Article
  • Title: Proteogenetic drug response profiling elucidates targetable vulnerabilities of myelofibrosis
  • Contributor: Wildschut, Mattheus H. E.; Mena, Julien; Dördelmann, Cyril; van Oostrum, Marc; Hale, Benjamin D.; Settelmeier, Jens; Festl, Yasmin; Lysenko, Veronika; Schürch, Patrick M.; Ring, Alexander; Severin, Yannik; Bader, Michael S.; Pedrioli, Patrick G. A.; Goetze, Sandra; van Drogen, Audrey; Balabanov, Stefan; Skoda, Radek C.; Lopes, Massimo; Wollscheid, Bernd; Theocharides, Alexandre P. A.; Snijder, Berend
  • imprint: Springer Science and Business Media LLC, 2023
  • Published in: Nature Communications
  • Language: English
  • DOI: 10.1038/s41467-023-42101-z
  • ISSN: 2041-1723
  • Keywords: General Physics and Astronomy ; General Biochemistry, Genetics and Molecular Biology ; General Chemistry ; Multidisciplinary
  • Origination:
  • Footnote:
  • Description: <jats:title>Abstract</jats:title><jats:p>Myelofibrosis is a hematopoietic stem cell disorder belonging to the myeloproliferative neoplasms. Myelofibrosis patients frequently carry driver mutations in either <jats:italic>JAK2</jats:italic> or Calreticulin (<jats:italic>CALR</jats:italic>) and have limited therapeutic options. Here, we integrate ex vivo drug response and proteotype analyses across myelofibrosis patient cohorts to discover targetable vulnerabilities and associated therapeutic strategies. Drug sensitivities of mutated and progenitor cells were measured in patient blood using high-content imaging and single-cell deep learning-based analyses. Integration with matched molecular profiling revealed three targetable vulnerabilities. First, <jats:italic>CALR</jats:italic> mutations drive BET and HDAC inhibitor sensitivity, particularly in the absence of high Ras pathway protein levels. Second, an MCM complex-high proliferative signature corresponds to advanced disease and sensitivity to drugs targeting pro-survival signaling and DNA replication. Third, homozygous <jats:italic>CALR</jats:italic> mutations result in high endoplasmic reticulum (ER) stress, responding to ER stressors and unfolded protein response inhibition. Overall, our integrated analyses provide a molecularly motivated roadmap for individualized myelofibrosis patient treatment.</jats:p>
  • Access State: Open Access