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 |
| DOI/URL: | |
| Notes: | Source: Scopus |
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