Targeting the CALR interactome in myeloproliferative neoplasms Journal Article

Authors: Pronier, E.; Cifani, P.; Merlinsky, T. R.; Berman, K. B.; Somasundara, A. V. H.; Rampal, R. K.; LaCava, J.; Wei, K. E.; Pastore, F.; Maag, J. L. V.; Park, J.; Koche, R.; Kentsis, A.; Levine, R. L.
Article Title: Targeting the CALR interactome in myeloproliferative neoplasms
Abstract: Mutations in the ER chaperone calreticulin (CALR) are common in myeloproliferative neoplasm (MPN) patients, activate the thrombopoietin receptor (MPL), and mediate constitutive JAK/STAT signaling. The mechanisms by which CALR mutations cause myeloid transformation are incompletely defined. We used mass spectrometry proteomics to identify CALR-mutant interacting proteins. Mutant CALR caused mislocalization of binding partners and increased recruitment of FLI1, ERP57, and CALR to the MPL promoter to enhance transcription. Consistent with a critical role for CALR-mediated JAK/STAT activation, we confirmed the efficacy of JAK2 inhibition on CALR-mutant cells in vitro and in vivo. Due to the altered interactome induced by CALR mutations, we hypothesized that CALR-mutant MPNs may be vulnerable to disruption of aberrant CALR protein complexes. A synthetic peptide designed to competitively inhibit the carboxy terminal of CALR specifically abrogated MPL/JAK/STAT signaling in cell lines and primary samples and improved the efficacy of JAK kinase inhibitors. These findings reveal what to our knowledge is a novel potential therapeutic approach for patients with CALR-mutant MPN.
Keywords: signal transduction; oncology; proteomics; drug therapy; hematology
Journal Title: JCI Insight
Volume: 3
Issue: 22
ISSN: 2379-3708
Publisher: Amer Soc Clinical Investigation Inc  
Date Published: 2018-11-15
Start Page: e122703
Language: English
DOI: 10.1172/jci.insight.122703
PUBMED: 30429377
PROVIDER: scopus
PMCID: PMC6302938
Notes: Source: Scopus
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