Mechanisms of human thrombopoietin receptor activation in myeloproliferative neoplasms
(2025)
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- Authors
- Supervisors
- Constantinescu, Stefan
- Abstract
- Proteins orchestrate essential biological functions, and their dysfunction underlies many diseases. One of these proteins, the Thrombopoietin Receptor (TpoR), is aberrantly activated in Myeloproliferative Neoplasms (MPNs) by somatic mutations in JAK2, calreticulin (CALR), or TpoR itself. This thesis takes a structural approach to dissect the mechanisms of TpoR activation in health and disease. In CALR mutant-positive MPNs, I resolved the structural basis of the CALR-TpoR interaction and identified the transferrin receptor (TFRC) as a co-secreted partner that stabilizes plasmatic mutant CALR, extending its pathogenic activity. In JAK2 V617F-positive MPNs, I demonstrated that TpoR dimers adopt a conformation distinct from that adopted in physiological condition, enabling selective targeting of the pathological state. Finally, using a novel mouse model, I delineated TpoR-dependent and -independent consequences induced by JAK2 V617F. These insights pave the way for therapies that specifically target pathological TpoR activation in MPNs.
- Affiliations
Citations
Papadopoulos, N. (2025). Mechanisms of human thrombopoietin receptor activation in myeloproliferative neoplasms. https://hdl.handle.net/2078.5/256650