Lysosomal Degradation Pathways Target Mutant Calreticulin and the Thrombopoietin Receptor in Myeloproliferative Neoplasms

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 MPN patients with CRT mutations display low cell surface MPL. Co-expression of MPL with an MPN-linked CRT mutant (CRT Del52 ) reduces cell surface MPL expression, indicating the involvement of induced protein degradation, a better understanding of which could lead to new therapies. We show that lysosomal degradation is relevant to the turnover of both CRT Del52 and MPL. Drug-mediated activation of lysosomal degradation reduces CRT Del52 and MPL expression, with parallel inhibition of CRT Del52 -induced cell proliferation and stem cell colony formation. Thus, reduced surface MPL, a marker of platelets from MPN patients with CRT mutations, results from mutant CRT-induced lysosomal degradation of MPL. Drug-induced activation of lysosomal degradation compromises the pathogenic effects of CRT Del52 , which can be further exploited for therapeutic interventions.