Proteogenetic drug response profiling elucidates targetable vulnerabilities of myelofibrosis

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, Michael S. Bader, Patrick G. A. Pedrioli, Sandra Goetze, Audrey Drogen, Stefan Balabanov, Radek C. Skoda, Massimo Lopes, Bernd Wollscheid (), Alexandre P. A. Theocharides () and Berend Snijder ()
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Mattheus H. E. Wildschut: ETH Zurich
Julien Mena: ETH Zurich
Cyril Dördelmann: University of Zurich
Marc Oostrum: ETH Zurich
Benjamin D. Hale: ETH Zurich
Jens Settelmeier: ETH Zurich
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
Sandra Goetze: ETH Zurich
Audrey Drogen: ETH Zurich
Stefan Balabanov: University Hospital Zurich
Radek C. Skoda: University Hospital Basel and University of Basel
Massimo Lopes: University of Zurich
Bernd Wollscheid: ETH Zurich
Alexandre P. A. Theocharides: University Hospital Zurich
Berend Snijder: ETH Zurich

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-42101-z

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