1016 – FINE-TUNING TPO-MPL ACTIVITY TO CONTROL HEMATOPOIESIS

Abstract

Thrombopoietin (TPO), acting via its receptor (MPL), is a master regulator of hematopoiesis and an exemplar pleiotropic cytokine – supporting HSC maintenance and driving megakaryocyte differentiation. The importance of TPO signalling is exemplified by human diseases; activating mutations in MPL or associated proteins JAK2 and CALR, lead to sustained MPL activation and myeloid malignancy, whereas loss-of-function mutations cause thrombocytopenia, HSC depletion and bone marrow failure. Recently, we have re-defined the molecular mechanisms of MPL activation, demonstrating that the receptor is monomeric at the membrane and is dimerized by TPO. In the same study, we showed that JAK2V617F, the primary driver mutation in MPN development, was able to promote TPO-independent MPL dimerization, and now have data showing we can block MPL oncogenic activity by targeting the MPL extracellular domain.

Our understanding of the TPO-2xMPL complex was further improved when we solved the structure of the complex using cryo-electron microscopy. This has, for the first time, uncovered detailed information on molecular interactions between TPO and MPL, allowing us to manipulate these interactions to alter receptor activity and uncouple TPO pleiotropic activity. By engineering TPO variants, which can fine-tune signalling output, we now have the potential switch between the role of TPO in HSC maintenance and platelet production.