The thrombopoietin receptor : mechanisms of oncogenic activation and their inhibition through molecular interactions at the transmembrane domain. Implications for myeloid neoplasms
(2024)
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- The thrombopoietin receptor (TPOR) is pivotal in classical myeloproliferative neoplasms essential thrombocythemia, polycythemia vera, and primary myelofibrosis, which all have in common the activation of the JAK-STAT pathway. TPOR itself can be mutated in these diseases or is required for JAK2 and CALR mutants to activate the pathway. Key findings of this thesis include : i) canonical S505N and W515K TPOR mutants differ in their dependence on extracellular domain (ECD) sequences for signaling, with S505N requiring ECD involvement; ii) JM ECD residues E488 and W491 are critical for pathogenic activation; iii) TPOR agonist eltrombopag requires residue W491 for activation, but not E488; iv) canonical TPOR mutations disrupt alpha helicity around W515 in the cytosolic JM domain, increasing flexibility and leading to JAK2 activation. These insights extend to non-canonical TPOR mutants and may play a role in the autonomous activation of other type I cytokine receptors EPOR and G-CSFR, especially regarding activating mutations immediately upstream of the TMD.
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Levy, G. (2024). The thrombopoietin receptor : mechanisms of oncogenic activation and their inhibition through molecular interactions at the transmembrane domain. Implications for myeloid neoplasms. https://hdl.handle.net/2078.5/238070