Type I but Not Type II Calreticulin Mutations Activate the IRE1α/XBP1 Pathway of the Unfolded Protein Response to Drive Myeloproliferative Neoplasms
Juan Ibarra, Yassmin A. Elbanna, Katarzyna Kurylowicz, Michele Ciboddo, Harrison S. Greenbaum, Nicole S. Arellano, Deborah Rodriguez, Maria Evers, Althea Bock-Hughes, Chenyu Liu, Quinn Smith, Julian Lutze, Julian Baumeister, Milena Kalmer, Kathrin Olschok, Benjamin Nicholson, Diane Silva, Luke Maxwell, Jonathan Dowgielewicz, Elisa Rumi, Daniela Pietra, Ilaria Carola Casetti, Silvia Catricala, Steffen Koschmieder, Sandeep Gurbuxani, Rebekka K. Schneider, Scott A. Oakes, Shannon E. Elf
Abstract
Approximately 20% of patients with myeloproliferative neoplasms (MPN) harbor mutations in the gene calreticulin (CALR), with 80% of those mutations classified 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 IRE1α/XBP1 pathway of the unfolded protein response. Genetic or pharmacologic inhibition of IRE1α/XBP1 signaling 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 differentiate between type I- versus type II-driven disease. To improve treatment strategies, it is critical to identify CALR mutation type-specific vulnerabilities. Here we show that IRE1α/XBP1 represents a unique, targetable dependency specific to type I CALR-mutated MPNs. This article is highlighted in the In This Issue feature, p. 265.