Journal
JCI INSIGHT
Volume 3, Issue 22, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.122703
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Funding
- Specialized Center of Research Program grant from the Leukemia and Lymphoma Society
- Cycle for Survival
- Memorial Sloan Kettering Cancer Center Support Grant [NIH P30 CA008748]
- Francois Wallace Monahan Fellowship
- Marie-Josee and Henry R. Kravis Center for Molecular Oncology
- [R35 CA197594-01A1]
- [R01 CA204396]
- [P01 CA108671]
- NATIONAL CANCER INSTITUTE [P30CA008748, R35CA197594, R01CA204396, P01CA108671] Funding Source: NIH RePORTER
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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.
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