Ludwig Link

Functional analysis suggests new approach to treating subset of myeloproliferative neoplasms

Stefan Constantinescu, Ludwig Cancer Research
Stefan Constantinescu

Unfettered signaling by the thrombopoietin receptor (TpoR) plays a central role in the development of slow-growing cancers known as myeloproliferative neoplasms (MPNs). It can be caused by mutations of the intracellular proteins JAK2 and calreticulin or of TpoR itself, all of which activate TpoR, causing uncontrolled proliferation and differentiation of hematopoietic (blood forming) stem cells and blood progenitor cells. The V617F mutation of JAK2 is the most common driver of MPNs and drugs that target JAK2 are used for therapy, though they are not specific to the mutant protein. TpoR targeting, on the other hand, has so far been poorly explored despite its central role in MPN pathology. Researchers led by the Ludwig Institute’s Stefan Constantinescu reported in an August issue of Blood their characterization of human TpoR activation induced by JAK2 V617F. They found that human TpoR (hTpoR) adopts different dimeric conformations upon thrombopoietin-induced versus JAK2 V617F-mediated activation and described the one responsible for its activation in complex with JAK2 V617F. They also showed that modulation of hTpoR conformations by point mutations allows specific inhibition of JAK2 V617F-driven activation without affecting normal Tpo-induced signaling. This suggests the drug-mediated tweaking of hTpoR conformation is a viable therapeutic strategy for JAK2 V617F-positive MPNs.

Modulation of human thrombopoietin receptor conformations uncouples JAK2 V617F-driven from cytokine-induced activation
Blood, 2023 August 24

 Back to November 2023 Ludwig Link

You are now leaving Ludwig Cancer Research's website and are going to a website that is not operated by the association. We are not responsible for the content or availability of linked sites. Do you wish to continue?