MPL encodes the thrombopoietin receptor (c-Mpl/TpoR), which serves as the primary regulator of hematopoietic stem cell (HSC) maintenance and megakaryocyte differentiation 1. Upon thrombopoietin (TPO) binding, MPL undergoes homodimerization and activates JAK2, creating docking sites for downstream signaling proteins including STAT5, SHIP/INPP5D, GRB2, SOS1 and PI3K 2. This activation triggers multiple signaling cascades including JAK/STAT, MAPK/ERK, and PI3K/AKT pathways, ultimately promoting megakaryocyte proliferation, survival, and differentiation leading to platelet production 31. Gene targeting studies have established the TPO/c-Mpl system as the major physiological regulator of steady-state megakaryocyte and platelet production, with an unexpected role in HSC regulation 1. MPL mutations are clinically significant as driver mutations in myeloproliferative neoplasms (MPNs), where they cause constitutive receptor activation and contribute to essential thrombocythemia and primary myelofibrosis 45. Loss-of-function mutations cause congenital amegakaryocytic thrombocytopenia, while gain-of-function mutations lead to thrombocytosis 6. The receptor's structural organization allows for therapeutic targeting, with engineered TPO variants showing potential for clinical applications in HSC transplantation 2.