The thrombopoietin receptor in myeloproliferative neoplasms: A unifying mechanism of disease pathogenesis and therapeutic targeting.
Key claim: All three MPN driver mutations (JAK2, CALR, and MPL) converge on enhanced thrombopoietin receptor (MPL) signaling, making the TPO/MPL axis the central molecular hub linking clonal hematopoiesis to thrombosis, hemorrhage, and fibrotic progression and a multi-faceted therapeutic target.
Abstract
The Philadelphia chromosome negative myeloproliferative neoplasms (MPNs), essential thrombocythemia, polycythemia vera, and primary myelofibrosis, are clonal hematopoietic stem cell disorders unified by constitutive thrombopoietin receptor (MPL) signaling. All 3 MPN driver mutations, JAK2, CALR, and MPL, converge on enhanced MPL signaling, establishing the thrombopoietin (TPO)/MPL axis as the central molecular hub linking clonal hematopoiesis to the cardinal manifestations of MPN, including thrombosis, hemorrhage, and fibrotic progression. As the principal regulator of hematopoietic stem cell maintenance and megakaryopoiesis and a key mediator of platelet priming, the TPO/MPL axis links stem cell biology to thromboinflammation and disease progression. This review summarizes the physiologic functions of the TPO/MPL axis, its dysregulation in MPN, and the downstream mechanisms linking aberrant MPL signaling to thrombosis, hemorrhage, and fibrotic progression. We further highlight recent advances in our understanding of TPO/MPL signaling in platelet biology, including its roles in platelet activation, metabolism, and thromboinflammation, and discuss emerging therapeutic strategies targeting the TPO/MPL pathway with the goal of simultaneously reducing thrombohemorrhagic complications, limiting fibrotic progression, and diminishing the malignant stem cell clone.
Why this matters
All three MPN driver mutations (JAK2, CALR, and MPL) converge on enhanced thrombopoietin receptor (MPL) signaling, making the TPO/MPL axis the central molecular hub linking clonal hematopoiesis to thrombosis, hemorrhage, and fibrotic progression and a multi-faceted therapeutic target.