Megakaryocyte maturation involves activation of the adaptive unfolded protein response

Endoplasmic reticulum stress triggers the unfolded protein response (UPR) to promote cell survival or apoptosis. Transient endoplasmic reticulum stress activation has been reported to trigger megakaryocyte production, and UPR activation has been reported as a feature of megakaryocytic cancers. However, the role of UPR signaling in megakaryocyte biology is not fully understood. We studied the involvement of UPR in human megakaryopoiesis using PMA (phorbol 12-myristate 13-acetate)-induced maturation of megakaryoblastic cell lines and thrombopoietin-induced differentiation of human peripheral blood-derived progenitors. Our results demonstrate that the adaptive UPR is a feature of megakaryocytic maturation, independent of ER stress-induced apoptosis, with the IRE1α UPR pathway being particularly important. Differentiation did not alter the ability of megakaryocytic cells to respond to the endoplasmic reticulum stressors DTT or thapsigargin. However, thapsigargin, but not DTT, inhibited differentiation, consistent with the involvement of Ca2+ signaling in megakaryopoiesis. ### Competing Interest Statement The authors have declared no competing interest.