MPL encodes the thrombopoietin receptor, a cell-surface cytokine receptor essential for hematopoietic stem cell renewal and megakaryocyte differentiation. Upon binding thrombopoietin, MPL rapidly phosphorylates and activates JAK2, which recruits downstream signaling proteins including STAT5, PI3K, and GRB2 to drive megakaryocyte proliferation, survival, and differentiation, ultimately increasing platelet production 1. The receptor can generate multiple protein isoforms through alternative splicing, including forms with distinct cytoplasmic domains and a putative soluble variant; isoform stoichiometry regulates the balance between hematopoietic stem cell quiescence and proliferation 2. MPL mutations drive myeloproliferative neoplasms (MPN), particularly essential thrombocythemia and primary myelofibrosis, by causing constitutive receptor activation and abnormal thrombopoietin signaling 3. Loss-of-function mutations cause congenital amegakaryocytic thrombocytopenia, whereas activating mutations increase thrombocytosis. At the population level, gnomAD v4.1 classifies this gene as LoF-tolerant (LOEUF=1.02) because heterozygous carriers are viable; this is distinct from the 210 pathogenic variants documented in ClinVar. Clinically, multiple thrombopoietin receptor agonists—including eltrombopag, romiplostim, and avatrombopag—are approved to treat thrombocytopenia across diverse conditions 4. Emerging research reveals that engineered thrombopoietin variants can selectively bias signaling toward megakaryopoiesis while minimizing hematopoietic stem cell expansion, offering improved therapeutic approaches for cell transplantation.