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

Abstract

Abstract Somatic 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 mutant CRT-expressing patients with MPN display low cell surface MPL. Additionally, coexpression of MPL with an MPN-linked CRT mutant (CRTDel52) reduces cell surface MPL, suggesting that CRTDel52 may induce MPL degradation. We show that lysosomal degradation is relevant to the turnover of CRTDel52 and MPL. Furthermore, CRTDel52 increases the lysosomal localization and degradation of MPL. Mammalian target of rapamycin (mTOR) inhibitors reduce cellular CRTDel52 and MPL, secreted CRTDel52 levels, and impair 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 that induced degradation of CRTDel52 and MPL is an avenue for therapeutic intervention.