Mechanism of mutant CALR-induced MPN and approaches for therapeutic targeting. (A) A pathogenic binding interaction between MPL and mutant CALR leads to activated MPL-JAK/STAT signaling. 1. Mutant CALR traffics through the ER to bind to immature MPL. 2. Stabilized mutant calreticulin-MPL complex traffics to the cell surface. 3. Mutant CALR induces MPL-JAK/STAT signaling pathway activation. (B) Potential nodes for therapeutic intervention in mutant-CALR–driven MPN. (C) Strategies to induce T-cell–directed immune therapy against mutant-CALR–driven MPN. APC, antigen-presenting cell; MPL, major histocompatibility complex; TCR, T-cell receptor.