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Proteogenetic drug response profiling elucidates targetable vulnerabilities of myelofibrosis

Author

Listed:
  • Mattheus H. E. Wildschut

    (ETH Zurich
    ETH Zurich
    University Hospital Zurich)

  • Julien Mena

    (ETH Zurich)

  • Cyril Dördelmann

    (University of Zurich)

  • Marc Oostrum

    (ETH Zurich)

  • Benjamin D. Hale

    (ETH Zurich)

  • Jens Settelmeier

    (ETH Zurich
    Swiss Institute of Bioinformatics)

  • Yasmin Festl

    (ETH Zurich)

  • Veronika Lysenko

    (University Hospital Zurich)

  • Patrick M. Schürch

    (University Hospital Zurich)

  • Alexander Ring

    (University Hospital Zurich)

  • Yannik Severin

    (ETH Zurich)

  • Michael S. Bader

    (University Hospital Basel and University of Basel)

  • Patrick G. A. Pedrioli

    (ETH Zurich
    Swiss Institute of Bioinformatics
    ETH PHRT Swiss Multi-Omics Center (SMOC))

  • Sandra Goetze

    (ETH Zurich
    Swiss Institute of Bioinformatics
    ETH PHRT Swiss Multi-Omics Center (SMOC))

  • Audrey Drogen

    (ETH Zurich
    Swiss Institute of Bioinformatics
    ETH PHRT Swiss Multi-Omics Center (SMOC))

  • Stefan Balabanov

    (University Hospital Zurich)

  • Radek C. Skoda

    (University Hospital Basel and University of Basel)

  • Massimo Lopes

    (University of Zurich)

  • Bernd Wollscheid

    (ETH Zurich
    Swiss Institute of Bioinformatics)

  • Alexandre P. A. Theocharides

    (University Hospital Zurich)

  • Berend Snijder

    (ETH Zurich
    Swiss Institute of Bioinformatics)

Abstract

Myelofibrosis is a hematopoietic stem cell disorder belonging to the myeloproliferative neoplasms. Myelofibrosis patients frequently carry driver mutations in either JAK2 or Calreticulin (CALR) 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, CALR 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 CALR 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.

Suggested Citation

  • Mattheus H. E. Wildschut & Julien Mena & Cyril Dördelmann & Marc Oostrum & Benjamin D. Hale & Jens Settelmeier & Yasmin Festl & Veronika Lysenko & Patrick M. Schürch & Alexander Ring & Yannik Severin , 2023. "Proteogenetic drug response profiling elucidates targetable vulnerabilities of myelofibrosis," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42101-z
    DOI: 10.1038/s41467-023-42101-z
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