In healthy cells, CALR is an ER-resident chaperone protein, and the TPO-R requires cytokine binding to trigger activation of downstream signaling. In cells bearing an oncogenic CALR mutation (mutCALR), mutCALR protein loses its ER retention signal and binds to nascent TPO-R protein, forming a complex that travels to the cell surface, causing cytokine-independent receptor signaling in HSCs and MK lineage cells, resulting in a competitive advantage for the mutant HSC and its progeny. INCA033989 binds to the unique C-terminal tail of mutCALR protein, displayed on the surface of TPO-R–expressing cells (HSCs and MKs), and drives receptor internalization and inhibition of TPO-R signaling. The aim is to switch off the overactive signaling, deplete the mutCALR clone, and enable healthy hematopoiesis to recolonize. Figure created with biorender.com.