Targeting the CALR interactome in myeloproliferative neoplasms.
| Publication Type | Academic Article |
| Authors | Pronier E, Cifani P, Merlinsky T, Berman K, Somasundara A, Rampal R, LaCava J, Wei K, Pastore F, Maag J, Park J, Koche R, Kentsis A, Levine R |
| Journal | JCI Insight |
| Volume | 3 |
| Issue | 22 |
| Date Published | 11/15/2018 |
| ISSN | 2379-3708 |
| Keywords | Antineoplastic Agents, Calreticulin, Leukemia, Myeloproliferative Disorders |
| 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. |
| DOI | 10.1172/jci.insight.122703 |
| PubMed ID | 30429377 |
| PubMed Central ID | PMC6302938 |