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Clinical drug response and proteotype profiling elucidates targetable vulnerabilities of myelofibrosis

ABSTRACT: Myelofibrosis (MF) is a hematopoietic stem cell disorder belonging to the myeloproliferative neoplasms. MF patients frequently carry driver mutations in JAK2 and Calreticulin (CALR) and have limited therapeutic options. Here, we integrate ex vivo drug response and proteotype analyses across MF 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 therapeutic vulnerabilities. First, CALR mutations drive BET and HDAC inhibitor sensitivity, particularly in the absence of high MAPK-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 ER stress, responding to ER stressors and UPR inhibition. Overall, our integrated analyses provide a molecularly-motivated roadmap for individualized MF patient treatment.

INSTRUMENT(S): Orbitrap Fusion Lumos, Q Exactive HF-X, Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): T Cell, Granulocyte, Cell Culture, Hematopoietic Progenitor Cell Antigen Cd34 (human), Blood

DISEASE(S): Essential Thrombocythemia,Myelofibrosis,Myeloproliferative Neoplasm

SUBMITTER: Mattheus Wildschut

LAB HEAD: Berend Snijder

PROVIDER: PXD036075 | Pride | 2023-10-12

REPOSITORIES: Pride

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