Lysosomal degradation targets mutant calreticulin and the thrombopoietin receptor in myeloproliferative neoplasms

Abstract

AbstractSomatic mutants of calreticulin (CRT) drive myeloproliferative neoplasms (MPNs) via binding to the thrombopoietin receptor (MPL) and aberrant activation of the JAK/STAT pathway. Compared with healthy donors, platelets from patients with MPN and CRT mutations display low cell surface MPL. Additionally, coexpression of MPL with an MPN–linked CRT mutant (CRTDel52) reduced cell surface MPL, suggesting that CRTDel52 may induce MPL degradation. We showed that lysosomal degradation is relevant to the turnover of CRTDel52 and MPL. Furthermore, CRTDel52 increased the lysosomal localization and degradation of MPL. Mammalian target of rapamycin (mTOR) inhibitors reduced cellular CRTDel52 and MPL, secreted CRTDel52 levels, and impaired CRTDel52–mediated cell proliferation. mTOR inhibition also reduces colony formation and differentiation of CD34+ cells from patients with MPN but not from healthy donors. Together, these findings indicate that low-surface MPL is a biomarker of mutant CRT-mediated MPN and induces the degradation of CRTDel52 and MPL as an avenue for therapeutic intervention.