Type I but Not Type II Calreticulin Mutations Activate the IRE1 a /XBP1 Pathway of the Unfolded Protein Response to Drive Myeloproliferative Neoplasms

Approximately 20% of patients with myeloproliferative neoplasms (MPN) harbor mutations in the gene calreticulin (CALR), with 80% of those mutations classifi ed as either type I or type II. While type II CALR-mutant proteins retain many of the Ca2 + binding sites present in the wild-type protein, type I CALR-mutant proteins lose these residues. The functional consequences of this differential loss of Ca2+ binding sites remain unexplored. Here, we show that the loss of Ca2+ binding residues in the type I mutant CALR protein directly impairs its Ca2+ binding ability, which in turn leads to depleted endoplasmic reticulum (ER) Ca2+ and subsequent activation of the IRE1 alpha/XBP1 pathway of the unfolded protein response. Genetic or pharmacologic inhibition of IRE1 alpha/XBP1 signal-ing induces cell death in type I mutant but not type II mutant or wild-type CALR-expressing cells, and abrogates type I mutant CALR-driven MPN disease progression in vivo. SIGNIFICANCE: Current targeted therapies for CALR-mutated MPNs are not curative and fail to dif-ferentiate between type I-versus type II-driven disease. To improve treatment strategies, it is critical to identify CALR mutation type-specifi c vulnerabilities. Here we show that IRE1 alpha /XBP1 represents a unique, targetable dependency specifi c to type I CALR-mutated MPNs.