CALR encodes calreticulin, a calcium-binding chaperone protein primarily functioning in endoplasmic reticulum (ER) protein folding quality control and calcium homeostasis. In hematologic malignancies, CALR mutations serve as driver mutations in myeloproliferative neoplasms (MPNs), particularly essential thrombocythemia and primary myelofibrosis 1. These mutations result in a constitutively active MPL-JAK2-STAT5 pathway, leading to abnormal myeloid proliferation 2. CALR mutations are found in approximately 23% of MPN patients and represent the second most common driver after JAK2 mutations 3. Unlike JAK2 mutations which affect multiple cytokine receptors, CALR mutations specifically activate the MPL receptor, explaining their restriction to thrombocythemia and myelofibrosis rather than polycythemia vera 1. Beyond its role in cancer, calreticulin translocates to the cell surface during ER stress (ecto-calreticulin), where it serves as a danger signal recognized by the NK cell receptor NKp46, facilitating elimination of stressed or infected cells 4. Clinically, CALR mutations influence disease prognosis and treatment response, with mutation clearance after stem cell transplantation serving as a predictor of relapse risk and survival outcomes 5. Novel therapeutic approaches targeting mutant CALR, including monoclonal antibodies, show promise for selective treatment of CALR-mutated MPNs 6.