Proteogenetic drug response profiling elucidates targetable vulnerabilities of myelofibrosis

Author:

Wildschut Mattheus H. E.ORCID,Mena JulienORCID,Dördelmann CyrilORCID,van Oostrum MarcORCID,Hale Benjamin D.,Settelmeier JensORCID,Festl Yasmin,Lysenko VeronikaORCID,Schürch Patrick M.ORCID,Ring Alexander,Severin Yannik,Bader Michael S.,Pedrioli Patrick G. A.,Goetze SandraORCID,van Drogen Audrey,Balabanov Stefan,Skoda Radek C.,Lopes MassimoORCID,Wollscheid BerndORCID,Theocharides Alexandre P. A.ORCID,Snijder BerendORCID

Abstract

AbstractMyelofibrosis 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.

Funder

Eidgenössische Technische Hochschule Zürich

Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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